At 9-under 201, Simpson was two strokes ahead of Danny Lee and Paul Casey after both of them made long birdie putts at the 18th hole. Stewart Cink and Kevin Kisner were three strokes off the lead.
After being among four players who shared the 36-hole lead, Simpson went ahead alone to stay after consecutive birdies to start his back nine. He made a 6-foot birdie putt at the 387-yard 10th and a 12-footer at the 630-yard 11th before finishing with seven consecutive pars.
It is only the second time in 12 years at Colonial for the 54-hole leader to have more than a one-stroke advantage.
Defending champion Jordan Spieth shot a 68 with a caddie switch after making the turn, and was at 4 under.
Lee and Kisner were also tied for the second-round lead, along with Scott Piercy who shot a 72 to fall five strokes back.
