Fellow American Scott Piercy was best after firing a blistering, bogey-free round of nine-under-par 63 with compatriot JB Holmes and Germany's Alex Cejka two shots back with 65s at the Golf Club of Houston.
Mickelson, the 2011 Houston winner, likes to sharpen his tournament play the week before the major test at Augusta National and he got off to a fast start.
Beginning his round at the 10th, Mickelson birdied three of his first four holes and added two more birdies to make the turn in five-under 31. He got to seven-under before taking a bogey at the finish when he failed to get up-and-down from a bunker.
"If I can play well this week...it should be some good momentum for next week," said Mickelson.
Charles Howell III, Luke Guthrie and Shawn Stefani joined Mickelson at six under par.
Piercy, who also started on the back nine, used an even hotter streak to take charge as he ran off five consecutive birdies from the 18th and capped off the round with a birdie at his last hole.
The 36-year-old Piercy, frustrated in his recovery from surgery to repair a torn flexor in his right arm in February 2014, said he found his proper swing plane during a marathon practice session two days ago.
"In my 13th hour, something kind of clicked and I figured it out," Piercy said, adding, "On Wednesday I kind of ingrained it, kept working on it. And today was awesome, it really was. It's been two years since I've really put a clubface on a ball like I know how, like I feel like I should."
Seven players were bunched at five-under 67, including Spaniard Sergio Garcia, France's Victor Dubuisson, Canadian Graham DeLaet, 2012 winner Hunter Mahan and Matt Kuchar, who lost in a playoff here last year.
Sweden's Jonas Blixt, American Patrick Reed and 2009 champion Paul Casey of England were in a large group at 68. 

Latest News from Sports News Desk