His father, Silas Bryan, of Scots-Irish and English ancestry, was an avid Jacksonian Democrat. Silas won election to the Illinois State Senate, but was defeated for re-election in 1860. He won election as a state circuit judge, and in 1866 moved his family to a 520-acre (210.4 ha) farm north of Salem, living in a ten-room house that was the envy of Marion County.

Until age ten, Bryan was home-schooled, as many children were. The Bible and McGuffey Readers shaped his views that gambling and liquor were evil, sinful, and iniquitous. To attend Whipple Academy, which was attached to Illinois College, Bryan was sent to Jacksonville, Illinois, in 1874.

Born and raised in Illinois, Bryan moved to Nebraska in the 1880s. He won election to the U.S. House of Representatives in the 1890 elections, serving two terms before his defeat in the 1894 Senate elections. At the 1896 Democratic National Convention, Bryan delivered his "Cross of Gold speech" which attacked the gold standard and the eastern moneyed interests — Bryan was a supporter of the free silver movement (effectively, expansionary monetary policy). In a repudiation of incumbent President Grover Cleveland and his conservative Bourbon Democrats, the Democratic convention nominated Bryan for President, making Bryan the youngest major party presidential nominee in U.S. history. He was 36 years old at the time, one year older than the minimum age limit of 35. A supporter of bimetallism, Bryan was also nominated by the Populist Party and the Silver Republican Party. In the intensely fought 1896 presidential election, Republican nominee william McKinley emerged triumphant. With over 500 speeches in 1896, Bryan invented the national stumping tour in an era when other presidential candidates stayed home.

Mary also became a Lawyer, and collaborated with Bryan on all his speeches and writings. He practiced law in Jacksonville from 1883 to 1887, then moved to the boom city of Lincoln, Nebraska. In Lincoln, he was raised a Master Mason in Lincoln Lodge 19, A.F. & A.M. Bryan also met James Dahlman in Lincoln, and they became lifelong friends. As chairman of the Nebraska Democratic Party, Dahlman would help carry Nebraska for Bryan in two presidential campaigns. Even when Dahlman became closely associated with Omaha's vice elements, including the breweries, as the city's eight-term mayor, he and Bryan maintained a collegial relationship.

Following high school, he entered Illinois College, graduating as valedictorian in 1881. During his time at Illinois College, Bryan was a member of the Sigma Pi literary society. He studied law at Union Law College in Chicago (which later became Northwestern University School of Law). While preparing for the bar exam, he taught high school and met Mary Elizabeth Baird, a cousin of william Sherman Jennings; the latter was also his own first-cousin. Bryan and Mary Elizabeth Baird married on October 1, 1884, and they settled in Jacksonville, which at the time had a population of two thousand.

In the Democratic landslide of 1890, Bryan was elected to the U.S. House of Representatives from Nebraska's First Congressional District. The growing prohibitionist movement had entered the election of 1890 with its own slate of candidates. In the three-way race in the First Congressional District, Bryan received 6,713 more votes than his nearest opponent. This was a plurality of the vote and was 8,000 votes short of a majority. Bryan was elected, only the second Democrat to be elected to Congress in the history of Nebraska. In 1892, Bryan was re-elected by a 140-vote majority in a two-person race. He ran for the Senate in 1894, but a Republican landslide led to the Nebraska state legislature's choice of a Republican for the Senate seat (at that time, state legislatures elected their representatives to the US Senate).

In 1893, the repeal of the Sherman Silver Purchase Act had resulted in the collapse of the silver market. Bryan delivered speeches across the country for free silver from 1894 to 1896, building a grass-roots reputation as a powerful champion of the cause.

Bryan also formally received the nominations of the Populist Party and the Silver Republican Party. With the three nominations, voters from any party could vote for Bryan without crossing party lines. In 1896, the Populists rejected Bryan's Democratic running mate, Maine banker Arthur Sewall, and named as his running mate Georgia Populist Thomas E. Watson. People could vote for Bryan and Sewall (on the Democratic or Silver Republican lines), or for Bryan and Watson (on the People's Party line).

L. Frank Baum satirized Bryan as the Cowardly Lion in The Wonderful Wizard of Oz, published in 1900. Baum had been a Republican Activist in 1896 and wrote on McKinley's behalf.

In 1901 Bryan founded a weekly magazine, The Commoner, calling on Democrats to dissolve the trusts, regulate the railroads more tightly, and support the Progressive Movement. Bryan was not a stranger to editorial practices having worked at the Omaha World Herald from 1894 to 1896 this early work provided himself a foundation in publishing. From 1901 to 1923 Bryan would publish and edit The Commoner curating, at its peak, a circulation of nearly 275,000 copies annually across the United States. The paper revealed Bryan's evolving thoughts on political discourse. He regarded prohibition as a "local" issue and did not endorse a constitutional amendment until 1910. In London in 1906, he presented a plan to the Inter-Parliamentary Peace Conference for arbitration of disputes that he hoped would avert warfare. He tentatively called for nationalization of the railroads, then backtracked and called only for more regulation. His party nominated Bourbon Democrat Alton B. Parker in 1904, who lost to Roosevelt. For two years following this defeat, Bryan would pursue his public speaking ventures on an international stage. From 1904 to 1906, Bryan traveled globally, preaching, sightseeing with his wife Mary, lecturing, and all while escaping the political upheaval in Washington. Bryan crusaded as well for legislation to support introduction of the initiative and referendum as a means of giving voters a direct voice, making a whistle-stop campaign tour of Arkansas in 1910. Bryan's speech to the students of Washington and Lee University began the Washington and Lee Mock Convention.

Michael Kazin considers Bryan the first of the 20th century "celebrity politicians", better known for their personalities and communications skills than their political views. Bryan was never comfortable with the black community, and attacked Roosevelt in 1904 for inviting Booker T. Washington to the White House to further the social equality between the races; he supported disfranchisement of Southern blacks. Form and content mix uneasily in Bryan's politics. The content of his speeches leads in a direct line to the progressive reforms adopted by 20th century Democrats. But the form his actions took was a romantic invocation of the American past, a populist insistence on the wisdom of ordinary folk, and a faith-based insistence on sincerity and character.

In a 1905 speech, Bryan warned that "the Darwinian theory represents man reaching his present perfection by the operation of the law of hate, the merciless law by which the strong crowd out and kill off the weak. If this is the law of our development then, if there is any logic that can bind the human mind, we shall turn backward to the beast in proportion as we substitute the law of love. I choose to believe that love rather than hatred is the law of development."

The 1908 election was Bryan’s third attempt to gain the presidency. The Democrats nominated Bryan by a wide margin at the Democratic convention held in Denver and decided on John Kern, a Politician from Indiana, as his running mate. Bryan ran against the Republicans and Theodore Roosevelt’s hand-picked nominee william Howard Taft.

In his famous Chautauqua lecture, "The Prince of Peace" (1909), Bryan warned that the theory of evolution could undermine the foundations of morality. He concluded, "while I do not accept the Darwinian theory I shall not quarrel with you about it." Evoking the design argument, he said, "I have a right to assume, and I prefer to assume, a Designer back of the design— a Creator back of the creation." He repeated this lecture at Rio de Janeiro in Brazil in 1910.

For supporting Woodrow Wilson for the presidency in 1912, Bryan was appointed Secretary of State, the top cabinet position. For all his enormous influence in the Democratic Party, his two years as Secretary of State was the only time he served in a powerful office. Historian Richard Hofstadter comments:

Bryan is also remembered for his prophetic statement shortly after he became the Secretary of State in 1913: “I believe there will be no war while I am Secretary of State, and I believe there will be no war as long as I live.”

Wilson took his measure and only nominally consulted him, making all the major foreign policy decisions from the White House. In the civil war in Mexico in 1914, Bryan supported American military intervention.

Bryan tried to yoke the American credit to the Entente, saying "money is the worst of all contrabands because it commands everything else," but eventually yielded. He also pointed out that by traveling on British vessels, which were at risk of attack, "an American citizen can, by putting his own Business above his regard for this country, assume for his own advantage unnecessary risks and thus involve his country in international complications" Wilson's demands from Germany for "strict accountability for any infringement of [American] rights, intentional or incidental" after the sinking of the Lusitania troubled Bryan, who counseled an “evenhanded policy.” Bryan resigned in June 1915, protesting “… why be so shocked by the drowning of a few people, if there is to be no objection to starving a nation.”

Despite their differences, Bryan campaigned as a private citizen for Wilson's reelection in 1916. When war was declared in April 1917, Bryan wrote Wilson, "Believing it to be the duty of the citizen to bear his part of the burden of war and his share of the peril, I hereby tender my services to the Government. Please enroll me as a private whenever I am needed and assign me to any work that I can do." Wilson, however, did not allow the 57-year-old Bryan to rejoin the military, and did not offer him any wartime role.

One book Bryan read at this time convinced him that Darwinism emphasizing the struggle of races had undermined morality in Germany. Bryan was deeply influenced by the Darwinian Biologist Vernon Kellogg's 1917 book, Headquarters Nights: A Record of Conversations and Experiences at the Headquarters of the German Army in Belgium and France, which asserted (on the basis of a conversation with a reserve officer he called "Professor von Flussen") that most German intellectuals were totally committed to might makes right due to "whole-hearted acceptance of the worst of Neo-Darwinism, the Allmacht of natural selection applied to human life and society and Kultur" based solely on "violent and fatal competitive struggle", neglecting the ameliorating effects of other evolutionary factors such as altruism or mutual aid.

Bryan also read The Science of Power (1918) by British social theorist Benjamin Kidd, which credited the philosophy of Friedrich Nietzsche with German nationalism, materialism, and militarism. He described this as the working out of the social Darwinian hypothesis.

In 1920, Bryan told the World Brotherhood Congress that the theory of evolution was "the most paralyzing influence with which civilization has had to deal in the last century" and that Nietzsche, in carrying the theory of evolution to its logical conclusion, "promulgated a philosophy that condemned democracy,... denounced Christianity,... denied the existence of God, overturned all concepts of morality,... and endeavored to substitute the worship of the superhuman for the worship of Jehovah."

The campaign kicked off in October 1921, when the Union Theological Seminary in Richmond, Virginia, invited Bryan to deliver the James Sprunt Lectures. In his lecture entitled "The Origin of Man", Bryan asked, "what is the role of man in the universe and what is the purpose of man?" For Bryan, the Bible was absolutely central to answering this question, and moral responsibility and the spirit of brotherhood could rest only on belief in God.

In his efforts to publicize his cause, Bryan joined the American Association for the Advancement of Science in 1924 and attended the annual meeting. A featured session at the meeting was a debate on biological evolution between Bryan and Edward Loranus Rice, a developmental Biologist from the Methodist-associated Ohio Wesleyan University.

In the days following the Scopes trial Bryan traveled hundreds of miles, delivering speeches in multiple towns. On Sunday, July 26, 1925, he returned from Chattanooga, Tennessee, to his home in Dayton. After attending church services he ate a large meal, then died during a nap that afternoon, five days after the trial's conclusion. When someone remarked to Darrow that Bryan died from a "broken heart", Darrow responded, "Broken heart, hell, he died of a busted belly!" Journalist H. L. Mencken, who disliked Bryan intensely, reportedly boasted to Darrow that "we killed the son of a bitch".

Bryan College, a Christian-oriented institution, opened in 1930 in Dayton as a lasting memorial to Bryan.

He also has a biographical part in "The 42nd Parallel" in John Dos Passos' USA Trilogy.

Inherit the Wind, a 1955 play by Jerome Lawrence and Robert Edwin Lee, is a highly fictionalized account of the Scopes Trial written in response to McCarthyism. A populist thrice-defeated Presidential candidate from Nebraska named Matthew Harrison Brady comes to a small town named Hillsboro in Tennessee to help prosecute a young Teacher for teaching evolution to his schoolchildren. He is opposed by a famous trial Lawyer, Henry Drummond (based on Darrow), and mocked by a cynical newspaperman (based on H.L. Mencken) as the trial assumes a national profile. A 1960 Hollywood film adaptation, written by the playwrights, was directed by Stanley Kramer and stars Spencer Tracy as Lawyer Henry Drummond and Fredric March as his friend and rival Matthew Harrison Brady.

The actor Ainslie Pryor played Bryan in a 1956 episode of the CBS anthology series You Are There that focuses on the Cross of Gold speech.

Many prominent Democrats have praised Bryan and his legacy. In 1962, former President Harry Truman said Bryan "was a great one—one of the greatest." Truman also claimed: "If it wasn't for old Bill Bryan, there wouldn't be any liberalism at all in the country now. Bryan kept liberalism alive, he kept it going." In 1900, Truman, aged 16, was a page at the Democratic National Convention in Kansas City. He heard Bryan speak and was deeply impressed. In 1900 Truman and his father "declared themselves thorough 'Bryan men'... Bryan remained an idol for Harry, as the voice of the Common man." Tom L. Johnson, the progressive mayor of Cleveland, Ohio, referred to Bryan's campaign in 1896 as "the first great struggle of the masses in our country against the privileged classes." In a 1934 speech dedicating a memorial to Bryan, President Franklin D. Roosevelt said "I think that we would choose the word 'sincerity' as fitting him [Bryan] most of all...it was that sincerity that served him so well in his life-long fight against sham and privilege and wrong. It was that sincerity which made him a force for good in his own generation and kept alive many of the ancient faiths on which we are building today. We...can well agree that he fought the good fight; that he finished the course; and that he kept the faith."

Bryan County, Oklahoma, is named after him. Bryan Medical Center (formerly BryanLGH Medical Center and Bryan Memorial Hospital) in Lincoln, Nebraska, Bryan College of Health Science, connected with the hospital in Lincoln, and Bryan College, located in Dayton, Tennessee, are also named for william Jennings Bryan. The william Jennings Bryan House in Nebraska was named a U.S. National Historic Landmark in 1963. A $4,000 scholarship for Creighton University students participating in Speech and Debate at the university is named after william Jennings Bryan. The Bryan Home Museum is a by-appointment only museum at his birthplace in Salem, Illinois. Salem is also home to Bryan Park and a large statue of Bryan. Omaha Bryan High School and Bryan Middle School in Bellevue, Nebraska, are named for him. He is also honored by having an elementary school in Mission, Texas, named after him, Bryan Elementary School on a street named after him, Bryan Street. His home at Asheville, North Carolina, from 1917 to 1920, the william Jennings Bryan House, was listed on the National Register of Historic Places in 1983.

A statue of Bryan represents the state of Nebraska at the National Statuary Hall in the United States Capitol, as part of the National Statuary Hall Collection. Bryan was named to the Nebraska Hall of Fame in 1971. A bust of him was dedicated as part of the Hall of Fame in 1974 which currently resides, like other members of the hall of fame, in the Nebraska State Capitol.

In 2013, Bryan was inducted into the Gennett Records Walk of Fame to commemorate his recording of the Cross of Gold speech.

According to Historian Ronald L. Numbers, Bryan was not nearly as much a fundamentalist as many modern-day creationists of the 21st century. Instead he is more accurately described as a "day-age creationist". Numbers says Bryan "not only read the Mosaic 'days' as geological 'ages' but allowed for the possibility of organic evolution—so long as it did not impinge on the supernatural origin of Adam and Eve."

Bryan was one of the best known orators of his time. He was a fixture in the Democratic Party, and a hero to the Common man. Starting with his Cross of Gold speech, Bryan brought the Populists into the Democratic Party. A strong believer in the power of government to improve people’s lives, Bryan expressed his belief to John Reed in 1916 that the government “may properly impose a minimum wage, regulate hours of labor, pass usury laws, and enforce inspection of food, sanitation and housing conditions.” Bryan became the bridge that brought different factions into the party, and paved the way for liberal Democrats such as Franklin D. Roosevelt with his New Deal legislation. As noted by Bryan's biographer Michael Kazin: