The 23-year-old from Florida has never played a PGA Tour event before, aside from the majors, but he made himself at home at CordeValle with an impressive round highlighted by an eagle at the par-five 15th which put him a shot clear of Jason Kokrak on 11 under.
Starting at the 10th he mixed a couple of early birdies with two dropped shots, but the eagle at 15 really kickstarted his round.
From there he picked up another six birdies against just one more bogey at the sixth.
Koepka has made an impression on the other side of the Atlantic, winning a clutch of second-tier Challenge events to earn his place on the full European Tour, but he is yet to shine in his home country.
A win in California would make him an immediate member of of the PGA Tour.
"It would be big," he told pgatour.com "Obviously it would be nice to win and get status over here.
"But if you play good, everything kind of takes care of itself."
Kokrak had an eagle at the ninth in a blemish-free 65 to sit 10 under, one clear of Robert Garrigus and Jim Herman.
Camilo Villegas was on his own in fifth on eight under.
Overnight leader Jeff Overton could only manage a one-over 72 to sit six under, alongside amongst others Andres Gonzales, who had a best-of-the-day nine-under-par 62.
Defending champion Jonas Blixt carded a 72 to make the cut with a shot to spare at one under overall, two behind Britons Brian Davis and Russell Knox.