Spieth put up a valiant effort in his title defence at Harbour Town Golf Links in South Carolina this past week, but ultimately the three-time major winner came up short to Fitzpatrick on the third extra hole.
Fitzpatrick, 28, hit an incredible shot from 186 yards to 12 inches to tap-in for birdie and the win.
But it could've ended so much earlier had Spieth not missed his birdie putt on the first playoff hole by the slimmest of margins.
Spieth shot a 5-under 66 Sunday on Hilton Head Island to join the reigning U.S. Open champ in extra holes. The first would be the par-4 18th they had just completed where both players had made par.
Both hit similar shots off the tee, but whereas Fitzpatrick hit his second just under 34 feet of the pin, Spieth was in much tighter with 12 feet for birdie.
Fitzpatrick did not hole his long putt attempt, giving Spieth an opening to end it early.
But while it looked like Spieth had the right line, ultimately the ball did not want to drop. His putt just barely lipped out and Spieth, quite understandably, reacted to the painful miss to win it.
"I don't know how the one on the first playoff hole didn't go in," Spieth told reporters following his loss to Fitzpatrick. "I think if I hit the same putt 10 times, it goes in eight times. It should go left at the very end there on the grain. It just wasn't meant to be."
As one of the PGA Tour's designated events this year, the RBC Heritage held one of the most lucrative purses of the season with $20m. First place won $3.6m, while second takes home over a million less with $2.18m.
By missing his 12-footer Sunday, it cost Spieth $1.42m and a chance to secure his 14th career PGA Tour victory.
On the second playoff hole, the par-3 17th, both players had similar birdie putts, but neither could find the bottom of the cup.
They went to a third, where Fitzpatrick was able to seal the deal.