As an amateur, in the welterweight division, he won three consecutive United States national championships and represented the U.S. at the 2012 Olympics, where he reached the quarter-finals.

[6][7] Spence lost in the quarter finals of the 2012 London Olympics to Russia's Andrey Zamkovoy and turned professional shortly afterwards.

In December 2012, Spence knocked out Richard Andrews at the Sports Arena in Los Angeles, California, which was part of undercard for Amir Khan's comeback fight against Carlos Molina.

Spence made his Showtime television debut on 27 June 2014 at the Hard Rock Hotel in Las Vegas in a 10-round fight against Ronald Cruz.

[12] On 13 December 2014, Spence beat Javier Castro by TKO in the 5th round at the MGM Grand Hotel and Casino in Las Vegas.

[13] On 11 April 2015, Spence defeated Samuel Vargas by TKO in Round 4 of 10 in a Premier Boxing Champions fight card at Barclays Center in Brooklyn, New York, bringing his record to 16–0.

[14] On May 16, it was announced that Spence would feature on the undercard of Shawn Porter vs. Adrien Broner on June 20 at the MGM Grand Arena.

[19][20] In October 2015 it was announced that Spence would fight at The Bomb Factory in Dallas on November 28 against Mexican boxer Alejandro Barrera (28-2, 18 KOs).

[32] Instead, it was confirmed that Spence Jr. would fight IBF #7 Leonard Bundu (33-1-2, 12 KOs) in the eliminator on August 21 at the Ford Amphitheater.

Brook's promoter Eddie Hearn mentioned talks were already ongoing with Spence's manager Al Haymon for a fight to take place possibly in the UK in May.

Hearn received an extension from the IBF for negotiations between himself and TGB Promotions boss Tom Brown, as they were progressing.

[44][45][46] At a press conference at Bramall Lane, Sheffield on March 22, the fight was officially announced to take place on May 27, 2017, live on Sky Box Office in the UK and Showtime in the US.

[47][48] In front of 27,000 fans, Spence dropped and eventually stopped Brook to win the IBF welterweight title after 11 rounds.

In a fight where mostly power shots were landed, Spence threw combinations to the head and to the body, gradually wearing down Brook.

[55] Dan Rafael revealed that Spence was promised a $3.5 million purse from his manager Al Haymon for his next fight.

[64] On January 23, 2018, the IBF sent a letter to TGB Promotions ordering Spence to make a mandatory defence against unbeaten prospect Carlos Ocampo (22-0, 13 KOs) next.

Because Ocampo was not rated in the top 2 in the IBF rankings at the time, at purse bids, he would be entitled to 15% rather than the 25% that a mandatory challenger receives.

[72] In front of a sellout crowd of 12,604 fans, Spence knocked Ocampo out in round 1 to retain his IBF title.

Spence stated he wanted to unify the division by going after the winner of the Shawn Porter vs. Danny Garcia, Keith Thurman and Terence Crawford.

[75] On October 25, 2018, BoxingScene.com reported that negotiations between Spence and Mikey Garcia (39-0,30 KOs) were progressing, with the fight likely to take place in February 2019 on Showtime PPV.

On October 30, Garcia vacated his IBF lightweight title and the purse bid for the potential Richard Commey fight was cancelled.

It was announced that the fight between Garcia and Spence would take place at the welterweight limit at the AT&T Stadium in Arlington, Texas on March 16, 2019, exclusively on FOX PPV.

Some welcoming the fight and praising Garcia for 'daring to be great' and some fans believed that the size difference would be too much as Spence is considered a big welterweight.

[84] Spence knocked Porter down in the eleventh round en route to a split decision victory, with the judges scoring it 116–111, 116–111, 112–115.

[87][88] On May 21, 2021, eight-division world champion Manny Pacquiao made the unexpected announcement on his social media that he and Spence would meet in the ring on August 21 in Las Vegas to face each other on Fox PPV.

[101] Spence Jr. and the WBO welterweight champion Terence Crawford came to an agreement on “all material terms” for a title unification, which was expected to take place on November 19.

[105][106] Finally, on May 25, 2023, it was confirmed that Spence Jr. would fight Terence Crawford for the undisputed welterweight titles on July 29, 2023, at the T-Mobile Arena in Las Vegas, Nevada.

[109] Spence was involved in a single-vehicle accident at 2:53 AM on October 10, 2019, in his hometown of Dallas, Texas, and was hospitalized in the intensive care unit.

[110][111] According to Dallas police, Spence's Ferrari 488 Spider was "traveling at a high rate of speed" and then "veered left over the center median onto the southbound lanes and flipped multiple times, ejecting the driver, who was not wearing a seatbelt.

but deleted this post after receiving backlash, as fans stated he was lucky to be alive and noted that he could have seriously hurt others due to his drunk driving.