The straight-hitting Englishman, who has yet to win a Major title, fired a five-under-par 67 at a rain-softened Augusta National where tough pin positions posed all sorts of problems for the game's leading players.
Westwood birdied the par-four 17th, then parred the difficult 18th to edge one ahead of South African Louis Oosthuizen, who stormed up the leaderboard with four birdies in the last five holes, and ice-cool Swede Peter Hanson.
Pony-tailed Spaniard Miguel Angel Jimenez, Italy's Francesco Molinari, Britain's Paul Lawrie, Americans Ben Crane, Bubba Watson and Jason Dufner carded 69s while tournament favourite Tiger Woods eked out a level-par 72 after bogeying 17 and 18.
Westwood, who finished second here in 2010 when he also opened with a 67, was delighted with his strong start in the year's first Major.
"There was no weakness out there today in my game. I hit it close, hit a lot of fairways and rolled in some nice putts," said the 38-year-old, who has six times finished in the top three at Majors.
"When this golf course is soft, it obviously gives you a bit more of a chance, but I think they were slightly worried about the scoring getting out of control, so they tucked a lot of the flags away.
"You can play your way out of a tournament in the first round, and I haven't done that, so I'm right where I want to be and looking forward to the next three days."
Oosthuizen, who romped to a seven-stroke victory in the 2010 Open, steadily worked his way up the leaderboard after making a slow start before ending his round with a 20-foot birdie putt at the 18th.
"This golf course, you've got to be very patient," the 29-year-old said after covering the back nine in three-under 33. "I played really well at the end."
Oosthuizen may have tamed the tricky 18th in the opening round but the hole took a brutal toll on many of the players and both Woods and Henrik Stenson came unstuck there.
Tournament favourite Woods bogeyed the hole after driving well left into the pine trees and Swede Stenson, who had led the field by two shots standing on the 18th tee, wound up with an ugly quadruple-bogey eight.
"I hit some of the worst golf shots I've ever hit today," four-times Masters champion Woods said after offsetting three birdies with three bogeys. "I squeezed a lot out of that round.
"I just hung in there and grinded my way around the golf course and stayed very patient, stayed in the moment. I could have shot one, maybe two better, but I got a lot out of that round."
Stenson, who won the biggest title of his career at the 2009 Players Championship, golf's unofficial fifth Major, raced to the turn in five-under 31 before picking up his sixth shot of the day at the par-four 10th.
However his 36th birthday ended on a bitter note with his nightmarish eight at the last which began with a wayward drive into the trees and ended with a missed three-foot putt.
"I don't think I've ever done that," said Stenson. "You make a little mistake and then you compound it with another one and it just keeps on snowballing. I got the snowman in the end."
South African Charl Schwartzel, who won last year's Masters title by two shots when he became the first champion to birdie the last four holes, opened with a 72.
US Open champion Rory McIlroy, who squandered a four-shot lead going into the final round here last year, recovered from a double-bogey at the first to shoot a 71.
British world number one Luke Donald returned a 75, and had to be cleared to keep playing in the Masters after officials investigated a mix-up over his score that turned out to be an administrative error.
Three-times Masters winner Phil Mickelson ended a roller-coaster day with a birdie at the last for a 74 that included a triple-bogey seven at the 10th.