Henry Wilson was born in Farmington, New Hampshire, on February 16, 1812, one of several children born to Winthrop and Abigail (Witham) Colbath. His father named him Jeremiah Jones Colbath after a wealthy neighbor who was a childless bachelor, vainly hoping that this gesture might result in an inheritance. Winthrop Colbath was a militia veteran of the War of 1812 who worked as a day laborer and hired himself out to local farms and businesses, in addition to occasionally running a sawmill.

After trying and failing to find work in New Hampshire, in 1833 Wilson walked more than one hundred miles to Natick, Massachusetts, seeking employment or a trade. Having met william P. Legro, a shoemaker who was willing to train him, Wilson hired himself out for five months to learn to make leather shoes called brogans. Wilson learned the trade in a few weeks, bought out his employment contract for $15, and opened his own shop, intending to save enough money to study law. Wilson had success as a shoemaker, and was able to save several hundred dollars in a relatively short time. This success gave rise to legends about Wilson's skill; according to one story that grew with retelling, he once attempted to make one hundred pairs of shoes without sleeping, and fell asleep with the one hundredth pair in his hand. Wilson's shoe making experience led to the creation of the political nicknames his supporters later used to highlight his working class roots—the "Natick Cobbler" and the "Natick Shoemaker".

On October 28, 1840, Wilson married Harriet Malvina Howe (1824–1870). They were the parents of a son, Henry Hamilton Wilson (1846–1866), who attended the Highland Military Academy in Worcester, Massachusetts.

During his Service in the Massachusetts legislature, Wilson took note that participation in the state militia had declined, and that it was not in a state of readiness. In addition to undertaking legislative efforts to provide uniforms and other equipment, in 1843 Wilson joined the militia himself, becoming a major in the 1st Artillery Regiment, which he later commanded with the rank of colonel. In 1846 Wilson was promoted to brigadier general as commander of the Massachusetts Militia's 3rd Brigade, a position he held until 1852.

Wilson was a member of the Massachusetts State Senate from 1844 to 1846 and 1850 to 1852. From 1851 to 1852 he was the Senate's President.

As early as 1845, Wilson had started to become disenchanted with the Whigs as the party attempted to compromise on the slavery issue, and as a Conscience Whig he took steps including the organization of a convention in Concord opposed to the annexation of Texas because it would expand slavery. As a result of this effort, in late 1845 Wilson and abolitionist John Greenleaf Whittier were chosen to submit in person a petition to Congress containing the signatures of 65,000 Massachusetts residents opposed to Texas annexation.

From 1848 to 1851 Wilson was the owner and Editor of the Boston Republican, which from 1841 to 1848 was a Whig outlet, and from 1848 to 1851 was the main Free Soil Party newspaper.

Having left the Whig Party, Wilson worked to build coalitions with others opposed to slavery, including Free Soilers, anti-slavery Democrats, Barnburners from New York's Democratic Party, the Liberty Party, the anti-slavery elements of the Whig Party, and anti-slavery members of the Know Nothing or Native American Party. Although Wilson's new political coalition was castigated by "straight party" adherents of the mainstream Democratic and Whig parties, in April 1851 it elected Free Soil candidate Charles Sumner to the U.S. Senate.

In 1852, Wilson was chairman of the Free Soil Party's national convention in Pittsburgh, which nominated John P. Hale for President and George Washington Julian for vice President. Later that year he was a Free Soil candidate for U.S. Representative, and lost to Whig Tappan Wentworth. He was a delegate to the state constitutional convention in 1853, which proposed a series of political and governmental reforms that were defeated by voters in a post-convention popular referendum. He ran unsuccessfully for Governor of Massachusetts as a Free Soil candidate in 1853 and 1854, but declined to be a candidate again in 1855 because he had his sights set on the U.S. Senate.

In his first Senate speech in 1855, Wilson continued to align himself with the abolitionists, who wanted to immediately end slavery in the United States and its territories. In his speech, Wilson said he wanted to abolish slavery "wherever we are morally and legally responsible for its existence", including Washington, D.C., Wilson also demanded repeal of the Fugitive Slave Act of 1850, believing the federal government should have no responsibility for enforcing slavery, and that once the act was repealed tensions between slavery proponents and opponents would abate, enabling those Southerners who opposed slavery to help end it in their own time.

On May 22, 1856, Preston Brooks brutally assaulted Senator Charles Sumner on the Senate floor, leaving Sumner bloody and unconscious. Brooks had been upset over Sumner's Crimes Against Kansas speech that denounced the Kansas-Nebraska Act. After the beating, Sumner received medical treatment at the Capitol, following which Wilson and Nathaniel P. Banks, the Speaker of the House, aided Sumner to travel by carriage to his lodgings, where he received further medical attention. Wilson called the beating by Brooks "brutal, murderous, and cowardly". Brooks immediately challenged Wilson to a duel. Wilson declined, saying that he could not legally or by personal conviction participate. In reference to a rumor that Brooks might attack Wilson in the Senate as he had attacked Sumner, Wilson told the press "I have sought no controversy, and I seek none, but I shall go where duty requires, uninfluenced by threats of any kind." The rumors proved unfounded, and Wilson continued his Senate duties without incident.

In June 1858 Wilson made a Senate speech in which he suggested corruption in the government of California and inferred complicity on the part of Senator william M. Gwin, a pro-slavery Democrat who had served as a member of Congress from Mississippi before moving to California. Gwin was backed by a powerful Southern coalition of pro-slavery Democrats called the Chivs, who had a monopoly on federal patronage in California. Gwin accused Wilson of demagoguery, and Wilson responded by saying he'd rather be thought a demagogue than a thief. Gwin then challenged Wilson to a duel; Wilson declined in the same terms he used to decline a duel with Preston Brooks. In fact neither Gwin nor Wilson wanted to follow through, and commentary about the dispute broke down along partisan lines. One pro-Gwin editorial called the insinuation that Gwin was corrupt "a most malignant falsehood", while a pro-Wilson editorial called his reluctance to take part in a duel evidence that he was "honest" and "conscientious", and had "more respect for the laws of this country than his adversary". After several attempts to find a face-saving compromise, Gwin and Wilson agreed to refer their dispute to three senators who would serve as mediators. william H. Seward, John J. Crittenden and Jefferson Davis were chosen, and produced an acceptable solution. At their instigation, Wilson stated to the Senate that he had not meant to impugn Gwin's honor, and Gwin replied by saying that he had not meant to question Wilson's motives. In addition, the mediators caused to be removed from the Senate record both Gwin's remarks about demagoguery and Wilson's suggestion that Gwin was a thief.

Among Wilson's authored and published works include: History of the Anti-Slavery Measures of the Thirty-seventh and Thirty-eighth Congresses, 1861–64 (1864); History of the Reconstruction Measures of the Thirty-ninth and Fortieth Congresses, 1865–68 (1868); and History of the Rise and Fall of the Slave Power in America, (three volumes, 1872–77). Reverend Samuel Hunt completed Volume III of History of the Rise and Fall of the Slave Power in America upon Wilson's sudden death in November 1875.

On July 8, 1862, Wilson drafted a measure that authorized the President to enlist African Americans who had been held in slavery and were deemed competent for military Service, and employ them to construct fortifications and carry out other military-related manual labor, the first step towards allowing African Americans to serve as Soldiers. President Lincoln signed the amendment into law on July 17. Wilson's law paid African Americans in the military $10 monthly, which was effectively $7 a month after deductions for food and clothing, while white Soldiers were paid effectively $14 monthly.

On February 17, 1863, Wilson introduced a bill that would federally fund elementary education for African American youth in Washington, D.C. President Lincoln signed the bill into law on March 3, 1863.

On June 15, 1864, Wilson succeeded in adding a provision to an appropriations bill which addressed the pay disparity between whites and blacks in the military by authorizing equal salaries and benefits for African American Soldiers. Wilson's provision stated that "all persons of color who had been or might be mustered into the military Service should receive the same uniform, clothing, rations, medical and hospital attendance, and pay" as white Soldiers, to date from January 1864.

During the Civil War, the younger Wilson attended the United States Naval Academy, but left before graduating in order to accept a commission in the Union Army. He attained success in the 31st and 104th Regiments of United States Colored Troops, and was promoted to lieutenant colonel and second-in-command of the 104th in July 1865. After the war he accepted a commission as a second lieutenant in the regular Army's 6th Cavalry Regiment, and served until his death from a ruptured appendix in 1866. Camp Wilson, an Army post in Texas was named for Henry H. Wilson; it was later renamed Fort Griffin.

Wilson actually desired to be Vice President. During his speech-making tour of the South, Wilson moderated his tougher Reconstruction ideology, advocating a biracial society, while urging African Americans and their white supporters to take a conciliatory and peaceful approach with Southern whites who had favored the Confederacy. Radicals, including Benjamin Wade, were stunned by Wilson's remarks, believing blacks should not be subject to their former white owners. At the Republican Convention, Wilson, Wade and others competed for the Vice Presidential nomination, and Wilson had support among Southern delegates, but he failed to win after five ballots. Wade was also unable to win the convention vote, and Wilson's delegates eventually switched their votes to Speaker of the House Schuyler Colfax, who won the nomination and went on to win the general election with Grant at the head of the ticket. After Grant and Colfax won the 1868 election Wilson declined to serve as Secretary of War in Grant's cabinet due to his Desire to spend more time with Mrs. Wilson during her lengthy final illness.

In 1869 Henry and Harriet Wilson also became the de facto adoptive parents of a girl, Evangelina, who was born between 1864 and 1866, and took the name Eva Wilson. In a complicated series of events, in 1869 a woman named Caroline Vreeland met Wilson's sister-in-law Nancy Colbath, wife of his brother Samuel. Vreeland allowed Nancy Colbath to adopt the child, with the understanding that she would be raised by Henry Wilson and his wife. The child lived with the Wilsons until shortly before Mrs. Wilson's death. Nancy Colbath then kept the child, and received monthly payments from Henry Wilson for her support. Details later emerged which indicated the likelihood that Vreeland had obtained a baby girl from an unknown parent or parents in Boston in 1866 so that her sister could use the baby in an attempt to extort a man with whom she had had an affair. Vreeland went to prison for a stabbing in the early 1870s. The child continued to live with Wilson, and by 1874 he had asked Nancy Colbath to again be responsible for her. Wilson agreed to provide them a suitable home and financial support, but had not followed through by the time of his death.

Mrs. Wilson had died in 1870, so Senators had to rely on Wilson's word and that of Ames, who corroborated Wilson. The Senate accepted Wilson's explanation, and took no action against him, but his reputation for integrity was somewhat damaged because of his initial denial and later admission, though not sufficiently enough to prevent him from becoming Vice President the following month.

During the 1872 campaign, Wilson's reputation for honesty was marred by a September New York Sun article which indicated that he was involved in the Crédit Mobilier scandal. Wilson was one of several Representatives and Senators (mostly Republicans), including Colfax, who were offered (and possibly took) bribes of cash and discounted shares in the Union Pacific Railroad's Crédit Mobilier subsidiary from Congressman Oakes Ames during the late 1860s in exchange for votes favorable to the Union Pacific during the building of the First Transcontinental Railroad.

Wilson's ceremonial duties and work on History of the Rise and Fall of the Slave Power in America kept him extremely busy, working late hours with little time to rest. In early May, 1873, Wilson attended funeral services for Salmon P. Chase in New York City. On May 19, 1873, he suffered a stroke which caused paralysis in his face, general weakness, and impaired speech. His Doctor ordered him to rest, but Wilson allowed reporters to see him. The public first took notice that Wilson was in ill health when he made an appearance in Boston on May 30, and reporters were informed that Wilson was unable to work or handle his correspondence. His health somewhat improved during September and October, and on November 25 Wilson returned to Washington for the opening of Congress. He was able to preside over the Senate from December 1 through December 9, 1873, but was unable to speak in public, including when he attended a Boston commemoration of the one hundredth anniversary of the Boston Tea Party.

Wilson remained in occasional ill health into 1874, but was able to attend funeral services for Charles Sumner in March. Throughout his remaining tenure, Wilson's Senate attendance was irregular due to his continued poor health. During periods when he was not ill, Wilson was also able to resume some of his ceremonial duties, including participating in a White House party for the King of Hawaii, David Kalākaua, in December 1874. When Free Soil and abolitionist colleague Gerrit Smith died in New York City on December 28, 1874, Wilson traveled there to view the body and take part in funeral services.

Wilson continued to go through bouts of ill health in 1875. While working at the United States Capitol on November 10, 1875, he suffered what was believed to be a minor stroke, and was taken to the Vice President's Room to recuperate. Over the next several days, his health appeared to improve and his friends thought he was nearly recovered. However, on November 22 at 7:20 AM, Wilson suffered a fatal stroke while working at the Capitol. His remains were accorded the honor of lying in state in the Capitol rotunda.

Wilson requested that the executor of his will, nephew william L. Coolidge, use most of Wilson's estate to ensure that Wilson's mother in law was cared for, and that Eva receive an education and financial support. Wilson had given Coolidge Verbal instructions and letters in addition to his will, and the situation became complicated because Wilson's death occurred before he had incorporated these additional instructions into his will. Coolidge acted as a trustee for Eva, and by 1889, when she was more than 21 years old, she claimed she was entitled to the remainder of Wilson's estate. Other Wilson family members disagreed; because of the complexity of the details, Coolidge petitioned the Massachusetts courts for guidance. The courts found in favor of Eva, by then married and known as Eva Carpenter, and she received the bulk of the residue of the estate.

In 1891, the Henry Wilson school, a facility for black students, opened on what was then Central Street in the Washington County portion of the District of Columbia (now 17th Street in the Adams Morgan neighborhood). It was named for him in honor of his role emancipating the district's slaves. The school was closed in 1956 due to its small size, and shortly thereafter converted to the Morgan Annex, a satellite location of the adjacent Thomas P. Morgan School. The Morgan Annex was later closed; it was sold in 1989, and then reopened as the Morgan Annex Lofts condominiums.

Wilson's experience in the militia, Service with the 22nd Massachusetts, and chairmanship of the Military Affairs Committee provided him with more practical military knowledge and training than any other Senator. He made use of this experience throughout the war to frame, explain, defend and advocate for legislation on military matters, including enlistment of Soldiers and sailors, and organizing and supplying the rapidly expanding Union Army and Union Navy.

Two other former Vice Presidents died in the same year as Wilson – John C. Breckinridge and Andrew Johnson.

The rift between the Radicals, including Wilson, and President Johnson grew as Johnson attempted to implement his more lenient Reconstruction policies. Johnson vetoed the bill to establish the Freedmen's Bureau, as well as other Radical measures to protect African American civil rights—measures which Wilson supported. Wilson supported the Senate effort to impeach Johnson, saying that Johnson was "unworthy, if not criminal" in his conduct by resisting Congressional Reconstruction measures, many of which were passed over his vetoes. At the 1868 Senate trial Wilson voted for Johnson's impeachment, but Republicans fell one vote short of the two-thirds majority needed to remove Johnson from office. (With 36 "guilty" votes needed for removal, the Senate results were 35 to 19 on all three post-trial ballots.)

The Colbath family was impoverished and, after a brief elementary education, at the age of 10 Wilson was indentured to a neighboring farmer, where he worked as a laborer for the next 10 years. During this time two neighbors gave him books and Wilson enhanced his meager education by reading extensively on English and American history and biography. At the end of his Service he was given "six sheep and a yoke of oxen." Wilson immediately sold his animals for $85 (about $2,100 in 2018), which was the first money he had earned during his indenture.