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

ESPN.com reported that the scheduled February 9, 2013 bout between Danny Garcia and Zab Judah at the Barclays Center in Brooklyn, New York was moved to April 27, 2013 because of a rib injury sustained by Garcia. With Jacobs penciled in on the undercard fight for this event, his fight moved to April 27th as well. Jacobs defeated Keenan Collins with a round 4 knockout on that date.

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! on Fox Sports 1.

WBA (Regular) middleweight champion

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 dropped Fletcher in round 1 with a left hook and in round 5 with a right cross. With the win, Jacobs became a world champion. "It feels so great to win this belt," Jacobs said. "It's the greatest moment in my life." Jacobs stated that he wanted to fight Peter Quillin next.

Jacobs' first defense came against Caleb Truax, whom he comfortably outboxed for eleven rounds, until he scored a knockdown and got a stoppage on round 12.

Jacobs' then fought former light middleweight titlist Sergio Mora. Jacobs started the fight tentatively, but was able to time and counter Mora with a right hook that put the latter on the canvas. Mora was able to return the favor when Jacobs tried to apply pressure to get a quick stoppage. The fight would then be stopped when Mora retired after injuring his right foot in round 2. After the fight, Jacobs once again said he was looking to fight Quillin.

Jacobs vs. Quillin, Mora II

On December 5, 2015 Jacobs beat Peter Quillin by TKO in the first round. Jacobs landed a lead right hand that caught Quillin flush on the template and heavily rocked him. Jacobs then attempted to finish the fight landing nonstop hard combinations the whole round. He landed another big punch that saw Quillin staggering over to the ropes, at which point the referee saw that Quillin was highly disorientated and waved the fight off with no complaint from Quillin. Many, including Floyd Mayweather, felt that the fight was halted too early.

In September 2016, Jacobs rematched Sergio Mora. He complained that the fight was a step back for him, as he thought he'd beaten Mora convincingly the first time. On fight night, Jacobs scored two flash knockdowns in rounds 4 and 5 befre getting a dominant TKO win. Mora went down three times in round 7 before the referee halted the contest.

Jacobs vs Golovkin

Jacobs was engaged in negotiations with WBC, IBF, IBO and WBA (Super) middleweight champion Gennady Golovkin through 2016. Jacobs was Golovkin's mandatory as both fighters held WBA belts, as part of the WBA's stated plan to unify their belts. WBA president Gilberto Mendoza confirmed in an email to RingTV that a deal had to be made by 5pm on December 7th or a purse bid would be held on December 19th in Panama. Later that day, the WBA announced a purse bid would be scheduled with a minimum bid of $400,000, with Golovkin receiving 75% and Jacobs 25%. Although purse bids were announced, Loeffler stated he would carry on negotiations, hopeful that a deal would be reached before the purse bid. On December 17th, terms were finally agreed and it was officially announced that the fight would take place at Madison Square Gardn in New York City on March 18th, 2017. The fight would be shown on HBO PPV.