In the trenches of World War One, Johnson's name was used by British troops to describe the impact of German 150 mm heavy artillery shells which had a black colour. In his letters home to his wife, Rupert Edward Inglis (1863–1916), a former rugby international who was a Forces Chaplain, describes passing through the town of Albert:

Johnson made his debut as a professional boxer on November 1, 1898, in Galveston, Texas, when he knocked out Charley Brooks in the second round of a 15-round bout for what was billed as "The Texas State Middleweight Title". In his third pro fight on May 8, 1899, he battled "Klondike" (John W. Haynes or Haines), an African American heavyweight known as "The Black Hercules", in Chicago. Klondike (so called as he was considered a rarity, like the gold in the Klondike), who had declared himself the "Black Heavyweight Champ", won on a technical knockout (TKO) in the fifth round of a scheduled six-rounder. The two fighters met again in 1900, with the first contest resulting in a draw as both fighters were on their feet at the end of 20 rounds. Johnson won the second fight by a TKO when Klondike refused to come out for the 14th round. Johnson did not claim Klondike's unrecognized title.

In Joe R. Lansdale's short story The Big Blow, Johnson is featured fighting a white boxer brought in by Galveston, Texas's boxing fans to defeat the African American fighter during the 1900 Galveston Hurricane. The story won a Bram Stoker Award and was expanded into a novel.

On February 25, 1901, Johnson fought Joe Choynski in Galveston. Choynski, a popular and experienced heavyweight, knocked out Johnson in the third round. Prizefighting was illegal in Texas at the time and they were both arrested. Bail was set at $5,000 which neither could afford. The sheriff permitted both fighters to go home at night so long as they agreed to spar in the jail cell. Large crowds gathered to watch the sessions. After 23 days in jail, their bail was reduced to an affordable level and a grand jury refused to indict either man. However, Johnson later stated that he learned his boxing skills during that jail time. The two would remain friends.

Johnson beat former black heavyweight champ Frank Childs on October 21, 1902. Childs had twice won the black heavyweight title and continued to claim himself the true black champ despite having lost his title in a bout with George Byers and then, after retaking the title from Byers, losing it again to Denver Ed Martin. He still made pretence to being the black champ and claimed the unrecognized black heavyweight title as well. Johnson won by a TKO in the 12th round of the scheduled 20-rounder, when Childs's seconds signaled he couldn't go on. (He claimed he had dislocated his elbow.) The defeat by Johnson forever ended Childs's pretensions to the black heavyweight crown.

By 1903, though Johnson's "official" record showed him with nine wins against three losses, five draws and two no contests, he had won at least 50 fights against both white and black opponents. Johnson won his first title on February 3, 1903, beating Denver Ed Martin on points in a 20-round match for the World Colored Heavyweight Championship. Johnson held the title until it was vacated when he won the world heavyweight title from Tommy Burns in Sydney, Australia on Boxing Day 1908. His reign of 2,151 days was the third longest in the 60-year-long history of the colored heavyweight title. Only Harry Wills at 3,103 days and Peter Jackson at 3,041 days held the title longer. A three-time colored heavyweight champion, Wills held the title for a total of 3,351 days.

Jack Johnson fought Joe Jeanette a total of seven times, all during his reign as colored champ before he became the world's heavyweight champion, winning four times and drawing twice (three of the victories and one draw were newspaper decisions). In their first match in 1905, they had fought to a draw, but in their second match on 25 November 1905, Johnson lost as he was disqualified in the second round of a scheduled six-round fight. Johnson continued to claim the title because of the disqualification.

However, Johnson did fight former champion Bob Fitzsimmons in July 1907, and knocked him out in two rounds. There is a report that Johnson even fought and KO'd Jim Jeffries' brother Jack, and taunted him about it to force a fight, with no success.

His fight with Tommy Burns was turned into a contemporary documentary The Burns-Johnson Fight in 1908.

After Johnson's victory over Burns, racial animosity among whites ran so deep that it was called out for a "Great White Hope" to take the title away from Johnson. While Johnson was heavyweight champion, he was covered more in the press than all other notable black men combined. The lead-up to the bout was peppered with racist press against Johnson. Even the New York Times wrote of the event, "If the black man wins, thousands and thousands of his ignorant brothers will misinterpret his victory as justifying claims to much more than mere physical equality with their white neighbors." As title holder, Johnson thus had to face a series of fighters each billed by boxing promoters as a "great white hope", often in exhibition matches. In 1909, he beat Tony Ross, Al Kaufman, and the middleweight champion Stanley Ketchel.

The fight took place on July 4, 1910, in front of 20,000 people, at a ring built just for the occasion in downtown Reno, Nevada. Jeffries proved unable to impose his will on the younger champion and Johnson dominated the fight. By the 15th round, after Jeffries had been knocked down twice for the first time in his career, Jeffries' corner threw in the towel to end the fight and prevent Jeffries from having a knockout on his record. Johnson later remarked he knew the fight was over in the 4th round when he landed an uppercut and saw the look on Jeffries face, stating, "I knew what that look meant. The old ship was sinking." Afterwards, Jeffries was humbled by the loss and what he'd seen of Johnson in their match. "I could never have whipped Johnson at my best", Jeffries said. "I couldn't have hit him. No, I couldn't have reached him in 1,000 years."

In January 1911, Johnson married Etta Terry Duryea. A Brooklyn socialite and former wife of Clarence Duryea, she met Johnson at a car race in 1909. Their romantic involvement was very turbulent. Suffering from severe depression, she committed suicide in September 1912, shooting herself with a revolver.

On October 18, 1912, Johnson was arrested on the grounds that his relationship with Lucille Cameron violated the Mann Act against "transporting women across state lines for immoral purposes" due to her being an alleged prostitute. Her mother also swore formally that her daughter was insane. Cameron, soon to become his second wife, refused to cooperate and the case fell apart. Less than a month later, Johnson was arrested again on similar charges. This time, the woman, another alleged prostitute named Belle Schreiber, with whom he had been involved in 1909 and 1910, testified against him. In the courtroom of Kenesaw Mountain Landis, the Future Commissioner of Baseball who perpetuated the baseball color line until his death, Johnson was convicted by an all-white jury in June 1913, despite the fact that the incidents used to convict him took place before passage of the Mann Act. He was sentenced to a year and a day in prison.

In November 1913, the International Boxing Union had declared the world heavyweight title held by Jack Johnson to be vacant. The fight, scheduled for 10 rounds, was held on 19 December 1913 in Paris. It was the first time in history that two blacks had fought for the world heavyweight championship.

Jack Johnson wrote two memoirs of his life Mes combats in 1914 and Jack Johnson in the Ring and Out in 1927.

On April 5, 1915, Johnson lost his title to Jess Willard, a working Cowboy from Kansas who started boxing when he was twenty-seven years old. With a crowd of 25,000 at Oriental Park Racetrack in Havana, Cuba, Johnson was knocked out in the 26th round of the scheduled 45 round fight. Johnson, although having won almost every round, began to tire after the 20th round, and was visibly hurt by heavy body punches from Willard in rounds preceding the 26th-round knockout.

Johnson skipped bail and left the country, joining Lucille in Montreal on June 25, before fleeing to France. In order to flee to Canada to skip his bail, Johnson posed as a member of a black baseball team. For the next seven years, they lived in exile in Europe, South America and Mexico. Johnson returned to the U.S. on 20 July 1920. He surrendered to federal agents at the Mexican border and was sent to the United States Penitentiary, Leavenworth to serve his sentence September 1920 as Inmate #15461.

While incarcerated, Johnson found need for a tool that would help tighten loosened fastening devices, and modified a wrench for the task. He patented his improvements on April 18, 1922, as US Patent 1,413,121. He was released on 9 July 1921.

Johnson was referenced in the film Anchorman: The Legend of Ron Burgundy, and he is mentioned in the 1940 book Native Son by author Richard Wright. Furthermore, 41st street in Galveston is named Jack Johnson Blvd.

Little is written about his religious affiliations, though in 1943, Johnson attended at least one Service at the Angelus Temple in Los Angeles, California. In a public conversion, while Detroit, Michigan, burned in race riots, he professed his faith to Christ in a Service conducted by famous evangelist Aimee Semple McPherson. She embraced him as "he raised his hand in worship".

Johnson continued fighting, but age was catching up with him. He fought professionally until 1938 at age 60 when he lost 7 of his last 9 bouts, losing his final fight to Walter Price by a 7th-round TKO. It is often suggested that any bouts after the age of 40—which was a very venerable age for boxing in those days—not be counted on his actual record, since he was basically performing in order to make a living. He also indulged in what was known as "cellar" fighting, where the bouts, unadvertised, were fought for private audiences, usually in cellars, or other unrecognized places. There are photographs existing of one of these fights. Johnson made his final ring appearance at age 67 on November 27, 1945, fighting three one-minute exhibition rounds against two opponents, Joe Jeanette and John Ballcort, in a benefit fight card for U.S. War Bonds.

On 10 June 1946, Johnson died in a car crash on U.S. Highway 1 near Franklinton, North Carolina a small town near Raleigh, after racing angrily from a diner that refused to serve him. He was taken to the closest black hospital, Saint Agnes Hospital in Raleigh. He was 68 years old at the time of his death. He was buried next to Etta Duryea Johnson at Graceland Cemetery in Chicago. His grave was initially unmarked, but a stone that bears only the name "Johnson" now stands above the plots of Jack, Etta, and Irene Pineau.

Johnson was inducted into the Boxing Hall of Fame in 1954, and is on the roster of both the International Boxing Hall of Fame and the World Boxing Hall of Fame. In 2005, the United States National Film Preservation Board deemed the film of the 1910 Johnson-Jeffries fight "historically significant" and put it in the National Film Registry.

Folksinger and blues singer Lead Belly referenced Johnson in a song about the Titanic: "Jack Johnson wanna get on board, Captain said I ain't hauling no coal. Fare thee, Titanic, fare thee well. When Jack Johnson heard that mighty shock, mighta seen the man do the Eagle rock. Fare thee, Titanic, fare thee well" (The Eagle Rock was a popular dance at the time). In 1969, American folk singer Jaime Brockett reworked the Lead Belly song into a satirical talking blues called "The Legend of the S.S. Titanic." There is no convincing evidence that Johnson was in fact refused passage on the Titanic because of his race, as these songs allege.

Johnson's story is the basis of the play and subsequent 1970 movie The Great White Hope, starring James Earl Jones as Johnson (known as Jack Jefferson in the movie), and Jane Alexander as his love interest.

The end of Miles Davis's 1971 album titled A Tribute to Jack Johnson features the actor Brock Peters (as Johnson) saying:

In 2002, scholar Molefi Kete Asante listed Jack Johnson on his list of 100 Greatest African Americans.

Johnson is a major character in the novel The Killings of Stanley Ketchel (2005), by James Carlos Blake.

Wal-Mart created a controversy in 2006 when DVD shoppers were directed from Charlie and the Chocolate Factory and Planet of the Apes to the "similar item" Unforgivable Blackness: The Rise and Fall of Jack Johnson.

Atlanta-based "flower punk" rock band the Black Lips recorded a song on their 2009 album 200 Million Thousand called "Big Black Baby Jesus of Today" which features the lyric "You can't be the Jack Johnson of today/Big Black Baby Jesus on the way."

In the opening scene of Episode 6, Series 2 (2011), of the British drama Downton Abbey, Mary Crawley, pushing her wheelchair-bound cousin Matthew Crawley across the lawn in the Summer of 1918 says, "I shall have arms like Jack Johnson if I'm not careful."

In 2012, the City of Galveston dedicated a park in Johnson's memory as Galveston Island's most famous native son. The park includes a life-size, bronze statue of Johnson.

Racial tension was brewing leading up to the fight and to prevent any harm to either boxer, guns were prohibited within the arena as were the sale of alcohol and anyone under the effects of alcohol. Behind the racial attitudes being instigated by the media was a major investment in gambling for the fight with 10–7 odds in favor of Jeffries.

Johnson was an early Example of the Celebrity athlete in the modern era, appearing regularly in the press and later on radio and in motion pictures. He earned considerable sums endorsing various products, including patent medicines, and indulged several expensive hobbies such as automobile racing and tailored clothing, as well as purchasing jewelry and furs for his wives. He even challenged champion racer Barney Oldfield to a match auto race at the Sheepshead Bay, Brooklyn, New York one mile (1.6 km) dirt track. Oldfield, far more experienced, easily out-distanced Johnson, ending any thoughts the boxer might have had about becoming a professional driver. Once, when he was pulled over for a $50 speeding ticket (a large sum at the time), he gave the officer a $100 bill; when the officer protested that he couldn't make change for that much, Johnson told him to keep the change, as he was going to make his return trip at the same speed. Johnson was also interested in opera (his favorite being Il Trovatore) and in history — he was an admirer of Napoleon Bonaparte, believing him to have risen from a similar origin to his own. In 1920, Johnson opened a night club in Harlem; he sold it three years later to a gangster, Owney Madden, who renamed it the Cotton Club.

The Royale, a play by Marco Ramirez, uses the life of Jack Johnson as inspiration for its main character, Jay Jackson. It premiered in March 2016 at Lincoln Center Theater directed by Rachel Chavkin, and was nominated for a Drama Desk Awards for Outstanding Play, Outstanding Director of a Play, and a Special Drama Desk Award for Outstanding Ensemble.

The "Fight of the Century" earned Johnson $65,000 (over $1.7 million in 2017 dollars) and silenced the critics, who had belittled Johnson's previous victory over Tommy Burns as "empty", claiming that Burns was a false champion since Jeffries had retired undefeated. John L. Sullivan commented after the fight that Johnson won deservedly, fairly, and convincingly:

Mike Tyson, Harry Reid and John McCain have all lent their support to the campaign, starting a Change.org petition asking President Obama to posthumously pardon the world’s first African-American boxing champion of his racially motivated 1913 felony conviction.