Garnett, 30, carded a four-under 66 at the Colonial Country Club in Texas to sit at seven under, a shot ahead of countrymen Chris Stroud and Robert Streb.
A PGA Tour rookie, Garnett has one top-10 finish this season and looks set to double that tally after his first two rounds.
Stroud’s outstanding six-under 64 and Streb’s solid 68 saw them well-placed in a tie for second.
American overnight leader Dustin Johnson (70) is one of seven players sharing fourth at five under, including Englishman Brian Davis (67) and Australian Aaron Baddeley (67).
The United States’ Bo Van Pelt (68), Chad Campbell (66) and Jimmy Walker (68) and South African Tim Clark (68) are also in that group.
Garnett started his second round with an eagle at the par-five first before giving up one of those shots at the third.
But he birdied the eighth, 11th and 16th holes for a fine round, bettering his opening 67.
Stroud managed four birdies on his first nine holes ” the back nine ” and four more on the front nine to move into contention.
Streb was more consistent as he mixed three birdies with a bogey in his round.
Australian Adam Scott, in his first tournament as the world number one, produced a 68 to be at one under and tied for 36th.
Jordan Spieth (69), Jason Dufner (69) and Brandt Snedeker (66) are three of six players at four under.
Defending champion Boo Weekley (69) made the cut and is tied for 47th at even par.
Americans Matt Kuchar and Rickie Fowler and Argentine Angel Cabrera were among those to miss the cut.
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