[6] Pettis formerly fought in the Welterweight, Lightweight, and Featherweight divisions of the Ultimate Fighting Championship (UFC) and Professional Fighters League (PFL).

After compiling a 3-0 record as an amateur, he made his professional MMA debut in January 2007 and won via submission in 36 seconds.

[17] He was then expected to fight Rob McCullough at WEC 44 on November 18, 2009, but was pulled off the card with an undisclosed injury.

[18][19] Pettis suffered his first professional loss on December 19, 2009, at WEC 45, dropping a split decision to Bart Palaszewski.

[20][21] Pettis rebounded from the loss with a head-kick KO victory over Danny Castillo on March 6, 2010, at WEC 47, earning Knockout of the Night honors.

[22][23][24] Training for the fight, as well as Pettis's family life, were both documented on an episode of the MTV show World of Jenks.

[7] Pettis suffered almost no damage in the bout with Castillo and made a quick return at WEC 48 on April 24, 2010, against Alex Karalexis, replacing Zack Micklewright on short notice.

[27] Pettis surprised many by taking down Roller multiple times and frustrating him with fast-paced scrambles.

Late in the fifth round Pettis ran up the cage, jumped off it, then connected with a flying switch kick that knocked down Henderson.

[36] Pettis was expected to face the winner of Frankie Edgar and Gray Maynard, which took place at UFC 125.

[37] However, the bout was declared a draw, and Edgar–Maynard 3 was scheduled for UFC 130, but both fighters sustained injuries before the fight, which was postponed.

[38] Instead of waiting for the winner of Edgar/Maynard 3, Pettis faced Clay Guida on June 4 at The Ultimate Fighter 13 Finale.

[46] After spending the majority of 2012 recovering from a litany of injuries,[47][48][49] Pettis faced Donald Cerrone on January 26, 2013, at UFC on Fox 6.

[53] On February 5, it was announced that Pettis would not wait for a title shot at lightweight, and would instead be dropping down to 145 pounds to challenge featherweight champion, José Aldo on August 3 at UFC 163.

[56] Pettis defeated Henderson via armbar submission in the first round to claim the UFC Lightweight Title.

[57] Pettis was expected to make his first title defense against TJ Grant on December 14 at UFC on Fox 9.

[58] However, Grant revealed in mid-September that he had yet to be medically cleared after suffering a concussion in training and would not be eligible to compete on December 14.

[61] Pettis was selected to serve as a coach on The Ultimate Fighter 20, opposite Gilbert Melendez and the two would face each other at UFC 181 on December 6, 2014.

[62] Pettis won the fight via guillotine choke in the second round, becoming the first man to finish Melendez.

[73] On the heels of a three-fight losing streak, Pettis announced in June 2016 his intention to drop to featherweight for his next fight.

[83] Pettis lost the fight via submission due to a rib injury suffered from a body triangle applied by Poirier.

The shards of the shattered window cut Chiesa, who was deemed unfit to fight by the athletic commission.

[87] On April 6, 2018, UFC Featherweight Champion Max Holloway was declared medically unfit by the New York State Athletic Commission and was pulled from his main event fight against Khabib Nurmagomedov.

[104] Pettis faced Alex Morono at UFC Fight Night: Thompson vs. Neal on December 19, 2020.

[123] Pettis faced Chris Avila in a six-round light heavyweight bout at Honda Center in Anaheim, CA on July 6, 2024.

[125] Along with business partners Duke Roufus and Scott Joffe, Pettis owns the Roufusport MMA Academy and the Showtime Sports Bar in Milwaukee.

[126][127] Pettis along with Jon Jones, Urijah Faber, Joseph Benavidez, Mark Muñoz, Chad Mendes, and Scott Jorgensen starred in a Form Athletics (now owned by K-Swiss) commercial.

[130] In the fall of 2014, Pettis was voted to be the first UFC champion to appear on the cover of General Mills' Wheaties box wearing his belt.

[7] The episode gave an inside look into Pettis' fight preparations as well as giving insights into his family life.