It was the second time Pettis had taken a title from Henderson.
In 2010, Pettis (17-2) needed an incredible fifth-round highlight-reel kick off the cage to win the WEC lightweight title from Henderson (19-3). This time, he needed less than five minutes to take home the UFC's 155-pound title.
"It feels amazing to be here," Pettis said after having the belt wrapped around his waist at Milwaukee's BMO Harris Bradley Center. "I grew up coming to this arena and sitting in those nosebleeds. Milwaukee made Anthony Pettis. You really can't write a better story than what happened right here tonight."
Pettis looked like the stronger fighter from the start, defending multiple takedown attempts from Henderson while looking for opportunities to strike. It came late in the opening round, as Pettis landed a series of thunderous kicks to the body that took a visible toll on his opponent.
But as his confidence built, Pettis tried for an acrobatic leaping kick that came up short, allowing Henderson to push the action to the floor. Henderson wasn't out of trouble, even as he set up on top.
Pettis turned quickly for a submission attempt, turning immediately into an armbar that left Henderson trapped. As Pettis torqued the hold, Henderson verbally submitted. Pettis let go of the hold, but it took the crowd a moment to gather what happened. When the Milwaukee-born Pettis scaled the cage to celebrate, the arena erupted.
Pettis was awarded a US$50,000 "Submission of the Night" award for his effort.
After the win, Pettis called out UFC featherweight champion Jose Aldo and said he was willing to meet the Brazilian at either 145 or 155 pounds. However, UFC president Dana White revealed at the event's post-event press conference that Pettis suffered a left knee injury that he will need to address before booking any future contests.
The night's co-feature saw two of the sport's top heavyweights meet in a long-awaited matchup, though the contest between former UFC champions Josh Barnett (33-6) and Frank Mir (16-8) resulted in a somewhat unsettling finish.
Barnett rushed forward from the opening bell, charging with punches and knees as Mir tried to defend against the cage. After surviving the initial barrage, Mir settled into the clinch, where he looked to turn the momentum in his favour.
However, Barnett quickly turned up the pressure again and landed a big knee that sent Mir crashing to the canvas. Barnett looked to follow with punches on the floor, but referee Rob Hinds stepped in to wave off the fight at the 1:56 mark of the first.
Mir immediately popped up to his feet to protest the stoppage, but the call had been made. While the end was likely inevitable, the stoppage seemed a touch premature, and the crowd on hand booed the decision. Still, the result was a Barnett victory in his first UFC appearance since 2002.
"It felt great to get this win here in the UFC," said Barnett. "It's been a long time coming, and it's great to get this matchup with Frank.
"I actually do feel that it was an early stoppage. I would always prefer to get the clean finish."
UFC boss White also said he thought the fight was stopped prematurely but declined to speculate whether or not the promotion would book a rematch.
Featherweight contender Chad Mendes (15-1) earned one of the biggest wins of his career, earning an impressive TKO finish of an always durable Clay Guida (30-11).
Mendes was the better fighter from the start, patiently handling Guida's fast-paced attacks by avoiding leaping punches and easily turning aside any takedown attempts. But already up two rounds to none, Mendes refused to be content with a decision win and turned up the heat in the third.
A right hand stunned Guida and Mendes pounced with a flurry of brutal power shots inside until Guida collapsed to the floor, forcing referee Yves Lavigne to step in 30 seconds in to the final round.
Mendes has now earned four straight knockout wins since his January 2012 loss to champ Jose Aldo and hopes to book a rematch later this year. Meanwhile, Guida loses by knockout for the first time in his 18 UFC appearances.
"I feel like I have made as big of a statement as I possibly could in this division," Mendes said. "I wanted a knockout very badly, and I got it. I knew it was my best bet."
Mendes, who earned the evening's "Knockout of the Night" bonus for his win, said he believes he's deserving of another shot at the belt. UFC boss White said Mendes' place among a strong list of contenders at 145 pounds is uncertain but admitted, "I love this kid."
Fighting at heavyweight for the first time since 2008, former dual-division contender Brandon Vera (12-7) tried to use a movement-based strategy to outwork a bigger Ben Rothwell (33-9). While the strategy worked for the better part of two rounds, Vera's luck ran out in the third.
After chasing Vera for much of the contest, Rothwell finally snapped in the final round, wildly gesturing and bobbing his head before rushing forward with a barrage of heavy punches. Vera tried to defend against the cage, but the blows snuck through his defence and he toppled to the floor.
Rothwell followed to the floor and pounded away until referee Herb Dean waved off the fight at the 1:54 mark of the round.
"I think the best of me came out in that third round tonight," Rothwell said. "I've still got some things to do, but I've got a great training facility, coaches and training partners, and that all helped me."
In the night's first main-card contest, top featherweight contenders Dustin Poirier (14-3) and Erik Koch (13-3) combined for a thrilling affair that included an opening frame likely to wind up on some "Round of the Year" lists.
Both fighters came close to finishing the contest in the opening round, Poirier through devastating strikes and Koch with a triangle choke that his opponent later admitted nearly forced him to submit. Poirier took firm control of the momentum in the second round and seemed well on his way to victory, but Koch remained game until the very end, looking for a rear-naked choke in the final seconds of the third frame that he just couldn't quite finish.
In the end, it was Poirier who was awarded a unanimous-decision win, 29-28, 29-27 and 29-27.
"I was dominant in the first two rounds, but I made a mistake in the third and he capitalized," Poirier said after the win. "He's slick but not that strong. I knew I had hurt him a couple times, but he's a tough guy."
UFC 164 drew a reported 9,178 fans for a $907,116 live gate according to UFC officials.