Crenshaw's two-round total of 7-under 133 put him at the top after 36 holes for the first time since the 1995 Memorial Tournament. He leads Fred Funk (68) by one stroke headed into Saturday's third round.
The event at the Baltimore Country Club is the tour's final major this season.
"I'm pleased with the way I'm playing," Crenshaw said. "Not much explanation for it this week. I'm driving the ball well."
At 4-under 136, sharing fifth place, are Mark O'Meara (67), John Morse (68), Bernhard Langer (70) and Nick Price (66). Defending champion Loren Roberts joins six others at 1-under 139, good for 20th place.
Among Thursday's three leaders, Phil Blackmar shot 3-over 73 Friday, while both Bruce Fleisher and Des Smyth shot 5-over 75 and fell into 28th place at even-par 140.