Scott finished his first round birdie-birdie and also holed out for eagle at the par-4 seventh. His final putt moved him past England's David Howell, who had held a clubhouse lead of 5-under-par 66 for much of the afternoon.
Fredrik Jacobson of Sweden is alone in fourth place after a 4-under 67 -- one shot ahead of Rocco Mediate, Aaron Oberholser, Tom Lehman, Joey Sindelar, David Toms and Daisuke Maruyama.
With rainfall a frequent sight over the last week or so, Westchester Country Club's West Course was playing soft during the first round. The conditions allowed for better scoring.
'The softer golf courses get easier when they play that way,' acknowledged Scott. 'Although I think they took that into consideration when they were cutting the pins because there were some very tricky pins out there.'
Scott, the eighth-ranked player in the world, picked up his first birdie from a bunker at the par-5 fifth, but handed that shot right back at the par-3 sixth when he three-putted for his only bogey.
He moved back into red numbers when he knocked in a pitching-wedge from 99 yards out for eagle at the short, 350-yard seventh, then got to 3 under around the turn with a birdie at the par-5 ninth.
On the back nine, Scott made his move on Howell's clubhouse lead. At the par-4 12th, he chipped-in from about 15 yards for his third birdie.
Four consecutive pars followed before Scott finished birdie-birdie at 17 and 18 for the lead.
His birdie putt at the par-4 17th was set up by a lob-wedge. At the 526-yard finishing hole, Scott's birdie putt was straight but long -- and it had a beat on the hole the entire way.
'It was nice to make those two putts at 17 and 18,' Scott said, 'because I really hadn't made many putts all day.'
Scott hasn't held a first-round lead since the 2004 Players Championship, which he won for one of his three PGA TOUR victories.
He also led after the opening round of the Byron Nelson Championship last month, but finished third -- one of three top-5 finishes in his last three starts.
'If I keep giving myself chances, I'm pretty sure I'm going to win here,' said Scott, 25. 'That's the goal -- to get in position for a run on Sunday and then over to the U.S. Open next week.'
Including Scott, the ninth-ranked Toms and the 10th-ranked Howell, seven of the top 10 players in the world are here this week for the U.S. Open precursor -- something tournament organizers haven't been shy to advertise.
World No. 2 Phil Mickelson and fourth-ranked Vijay Singh are among a group tied for 22nd place at 1-under-par 70. Third-ranked Retief Goosen is tied for 44th place at even par, while seventh-ranked Sergio Garcia is two shots further back in 93rd place.
World No. 1 Tiger Woods continues to take time off following the death of his father, Earl, last month. Fifth-ranked Jim Furyk is out with a neck injury, and sixth-ranked Ernie Els is also absent.
Defending champion Padraig Harrington sputtered to a 3-over 74 and is in a tie for 117th place.