Spieth and his fellow American had finished at 13-under 271 at Harbour Town Golf Links and the duo both found sand with their approaches to the first extra hole, the par-4 18th.
But while Spieth splashed out to tap-in range, Cantlay drew a poor lie and made bogey.
It gave Spieth his 13th PGA Tour title and first since last April's Texas Open.
The 28-year-old started the day three back but charged up the board with eagles on the par 5s at 2 and 5.
Despite his recent habit of missing short putts which continued this week, he stayed in the hunt and birdied 13 and 18 to set the clubhouse target of 13-under.
It didn't look enough but only Cantlay could match it.
The Californian wobbled with a bogey at 14 but holed from eight feet at 17 to join the lead.
He'd birdied the 18th in each of the first three rounds but a par this time meant a playoff. And, for the second time this season, Cantlay came up short.
The Ryder Cup star also lost a playoff to Masters champion Scottie Scheffler at the Waste Management Phoenix Open.
No less than seven players finished in a tie for third, one shot back: Cam Davis, JT Poston, Cameron Young, Sepp Straka, Matt Kuchar, Harold Varner III and Shane Lowry.
Lowry looked in the box seat after reaching 14-under with a birdie at 11 but he found water at 14 to rack up a double bogey and couldn't find the necessary par breaker in the final four holes.
Straka will also be kicking himself for finishing one back.
The Austrian, who won the Honda Classic earlier this year, got to 13-under (the play-off number) after draining a 35-foot putt at 17 and found the middle of the fairway with his drive at 18.
But Straka played a loose approach and took three to get down from left of the green.
Varner reached 12-under at the turn but stayed there after a run of nine straight pars on the back nine.
Fate of the Masters contenders and big names
The rule that you should never back anyone at the Heritage who contended heavily at the Masters had mixed results this week.
Shane Lowry and Cameron Smith both finished third at Augusta so were prime candidates for those following past trends.
But, as noted, Lowry had a golden chance to win.
Perhaps his batteries were low when he found water with fives holes to go in the final round although that's clutching at straws maybe.
In truth, Lowry had a glorious opportunity to win.
But anyone who opposed Smith due to Augusta fatigue was proved correct as the Aussie missed the cut.
Other big names also underperformed this week and maybe some post-Masters fallout was why.
Dustin Johnson and Matt Fitzpatrick also missed the cut while Collin Morikawa (T26) and Justin Thomas (T35) both finished outside the top 25.