Nicknamed the "Miracle Man", Jacobs' career was almost cut short in 2011 due to osteosarcoma, a rare form of bone cancer.

He went on to make a full recovery after spending 19 months out of the sport, meanwhile recovering from severe operation-induced injuries generally perceived as crippling.

In July 2005 he faced Russian Matvey Korobov at the preliminaries of the 2005 Boxing World Cup, and lost via a third round stoppage.

In 2006, Jacobs won the United States Amateur middleweight championship, decisioning Shawn Porter in the finals, 32–21.

[8] Jacobs made his professional boxing debut on the undercard of Floyd Mayweather Jr. vs. Ricky Hatton, which took place on December 8, 2007, at the MGM Grand in Las Vegas, Nevada.

On April 27, 2009, Jacobs agreed to replace junior middleweight James Kirkland, who was arrested on a gun charge, to fight Mike Walker, who was coming off a victory over two-time world title challenger Antwun Echols.

[10] The fight took place on May 2, 2009, at the MGM Grand in Las Vegas, and Jacobs won by unanimous decision with scores of 80–72 from two judges and 79–73 from the other.

[11] On August 22, 2009, Jacobs defeated Ishe Smith by unanimous decision to win the NABO middleweight title.

On July 31, 2010, Jacobs faced undefeated Russian Dmitry Pirog for the vacant WBO middleweight championship.

[15] On October 20, 2012, having fully recovered from cancer, Jacobs made a successful return to professional boxing with a first-round knockout victory over Josh Luteran.

[19] On August 19, 2013, Jacobs captured the WBC Continental Americas middleweight title via third-round knockout of Giovanni Lorenzo during the premiere of Golden Boy Live!

[20][21] On August 9, 2014, Jacobs won the vacant WBA (Regular) middleweight title with a 5th-round TKO over Jarrod Fletcher at the Barclays Center in Brooklyn, New York.

Jacobs landed a lead right hand that caught Quillin flush on the temple and heavily rocked him.

[28] Jacobs was engaged in negotiations with WBC, IBF, IBO and WBA (Super) middleweight champion Gennady Golovkin through 2016.

[31] On December 17, terms were finally agreed and it was officially announced that the fight would take place at Madison Square Garden in New York City on March 18, 2017.

Golovkin's ring control, constant forward pressure and effective jab lead to a 115–112, 115–112, and 114–113 unanimous decision victory, ending his 23-fight knockout streak which dated back to November 2008.

[42] Jacobs dominated Arias from beginning to end and scored a flash knockdown in round 11 to win a unanimous decision 118–109, 119–108, and 120–107.

[45] In February 2018, after weeks of speculation, it was officially announced that Jacobs would fight Polish boxer Maciej Sulęcki (26–0, 10 KOs) on April 28 at the Barclays Center in New York City on HBO.

[45] On April 27, the IBF ordered Gennady Golovkin to defend his title against Ukrainian contender Sergiy Derevyanchenko (12–0, 10 KOs).

[55] On July 20, according to Ringtv, the fight would take place for the vacant IBF middleweight title on November 10, 2018 at the Nassau Veterans Memorial Coliseum, Uniondale, New York.

Canelo proved to be the more elusive and efficient of the two, winning the fight via unanimous decision, 116–112, 115–113 and 115–113 to unify the middleweight belts.

In a largely underwhelming fight, Jacobs, who came in as the heavy favorite, had a rough time against Rosado, and scored a narrow split-decision win.

[60] Jacobs lost to Shane Mosley Jr. by unanimous decision in a 10-round super middleweight bout at the Honda Center in Anaheim, California, on July 6, 2024, with the ringside judges scoring the fight 99-91, 99-91 and 100-90.