He posted a 19-under 197 total, one shot ahead of fellow Americans Martin Piller and Andrew Landry, and two in front of Scott Piercy and Spaniard Jon Rahm.
The 26-year-old Cook broke through for his maiden victory at the RSM Classic in Georgia in November and said he expected that experience would hold him in good stead on Sunday when everyone will play the same course, the Stadium at PGA West.
"I'm a lot more comfortable knowing I can have a lead and keep a lead until Sunday," he told Golf Channel. "I'm just excited to be in this situation again.
"It was hard to prepare for three golf courses in two days but I think I'm doing an alright job so far. Good ball striking, good putting equals low rounds."
Landry (70) stayed in contention as he remained bogey-free through 54 holes. He and Piercy (67) are both seeking their first tour victory.
Spanish world number three Rahm struggled with his swing but a 70 at the Stadium Course was enough to remain within striking distance.
"Things have been a little worse and worse (each round)," he said. "First day everything was outstanding. Yesterday my driver was a little shaky but my iron shots were perfect.
"Today my driver was shaky, my iron shots were shaky and a course like this is really punishing but luckily the holes I found the fairway I was able to convert and make birdies."
Rahm narrowly avoided major trouble at the water-surrounded par-three 17th when his ball took one bounce into the hazard, where it struck a rock and then ricocheted back towards the green.
Though still in the hazard, his ball was playable almost up against a rock but affording him a short backswing and while the recovery attempt was not without risk -- another player had attempted a similar shot only to get into further trouble -- Rahm chipped his ball out and two putted for bogey.
(Reporting by Andrew Both in Cary, North Carolina; Editing by Greg Stutchbury)
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