Kerr was a high school state champion in Ohio, wrestling for Toledo Waite. At Syracuse University, Kerr was the Division I champion at 190 pounds in 1992. Randy Couture, wrestling for Oklahoma State University, took second place. Kerr was also a Division I All-American in 1992. In 1994, Kerr was the USA Senior Freestyle Champion at 220 pounds. While training as an amateur wrestler, Kerr became interested in mixed martial arts as a way to earn money.

Kerr’s first professional MMA fight was at the World Vale Tudo Championship III, where he won three fights, one by TKO by strikes (in which he broke his hand but continued to fight), another opponent literally crawled out of the ring to avoid Kerr's brutal ground-and-pound, and the final match was a savage half hour brawl (with his broken hand) in which he punched, kneed , eye-gouged and elbowed his way to victory . Kerr had four impressive wins in the UFC with which he became UFC heavyweight champion , before fighting in Pride Fighting Championships in 1998. Kerr had a ground-and-pound fighting style where he would use takedowns to get his opponent onto the mat and then use strikes and submissions to try and finish the fight. Kerr’s final MMA win was at Pride 10 where he defeated Igor Borisov by submission. Four months later, at Pride 12, he lost to Igor Vovchanchyn by decision, in the rematch of a Pride 7 fight where Kerr had been illegally knocked out by knees to the head from Vovchanchyn. Kerr would then lose to Heath Herring at Pride 15 via TKO. This trend continued three years later in 2004 at his next match at Pride 27, where he was knocked out with a front guillotine choke while trying to take down his opponent with a hard slam, Yoshihisa Yamamoto.

In 2003, HBO aired a documentary titled "The Smashing Machine: The Life and Times of Mark Kerr." The program chronicles Kerr’s addiction to painkillers and the no-holds barred aspect of mixed martial arts. Ken Shamrock, Bas Rutten and Mark Coleman also appear in the film. In his return to mixed martial arts in 2006, Kerr, who has become a father since he last entered the ring, wants to abolish his image as "The Smashing Machine." After his unfortunate loss to Yoshihisa Yamamoto, Kerr was supposed to make his comeback against Wes Sims in the American Championship Fighting (ACF) on May 6, 2006 at the Denver Coliseum, but was not medically cleared to fight due to a hand injury.

On February 11, 2007, Kerr fought Mustafa Al Turk at Cage Rage 20 'Born 2 Fight'. Kerr started strong and threw a couple of good strikes , but after losing his footing on the mat from an attempted right high roundhouse kick he was mounted , stunned with a series of blows and submitted within the first round.

Kerr was also active in the ADCC (Abu Dhabi Combat Club) competitions, a submission wrestling organisation where strikes are not allowed. He wrestled there with other well known MMA fighters such as Mario Sperry, Josh Barnett, and Ricardo Arona. Kerr is a wrestler by background, but he's also skilled with submissions and submission defense. Kerr is also an avid powerlifter, he can Bench press 425 lb (192.5 kg) and Squat 550 lb (250 kg).