Simpson, 32, signed for a final round 73 for an 18-under tally at Ponte Vedre in Florida.
The North Carolina native was never headed since sharing the lead on day one and then storming five shots clear of his rivals on day two in shooting a course record-equalling 63.
Simpson then extended his lead during Saturday’s third round to a tournament record seven shots and while his final round lead had been cut to four shots through 10 holes he eventually sealed a fourth Tour victory.
Simpson teed-off on day four to be immediately under threat from playing partner Danny Lee, who soon cut Simpson’s lead to five with birdies at two and three.
Simpson stalled with six straight pars before a first birdie of his round at the par-4 seventh that took him to 20-under par.
However, Simpson gave the shot straight back in finding a greenside bunker right of the flag at the par-3 eighth hole but as Simpson headed to his final nine holes his biggest threat wasn’t Lee but double Players winning Tiger Woods.
Woods had produced a career-best TPC Sawgrass score of 65 on Saturday and then moved to 14-under through 12 holes thanks to six birdies.
It would be the highwater mark of Woods challenge after dropping a shot at 14 to fall back to 13-under par before then taking a double bogey in finding the water at the par-3 17th on route to a 69 and an eventual share of 11th place on 11-under.
Simpson dropped a second shot of his round at the 10th to be back to 18-under par but moved back to 20-under par with birdies at the two inward half par-5s, the 11th and 16th holes.
He proudly strode down the last leading by six shots only to find the water with his approach shot and eventually finish with a double-bogey 6 and win by four with an 18-under par tally.
“Man, it means everything to me. I feel like it’s my first win. I feel so similar to how I felt in Greensboro back in 2011,” he said.
“To win a major championship and a few other Tour events and then go – I guess it’s over four years without a win, I never doubted myself, but at the same time, that’s a long time.
“We train hard and practice hard to try to win, and so – there’s been some tough moments along the way, as I’ve shared with you guys this week, but to come here against this field and put up some good numbers the first three days and do what I needed to do today to get it done, I’m so happy.
“I definitely could not have done this without the team that I’ve put in place with my wife, my management, my trainer. There’s so many people that are part of what I do, day in, day out, just really thankful that everybody stayed with me and stayed positive throughout.”
Three players – South African Charl Schwartzel (66) and the American duo of Jimmy Walker (67) and Xander Schauffele (67) – shared second place on 14-under par.
Tiger Woods reached a share of third through 12 holes but then took a double-bogey 5 at the famed 17th in shooting a 69 and settled for a tie for 11th place on 11-under par.
“I didn’t play particularly well in the first couple days, but I turned it around this weekend and I got it rolling,” said Woods.
“I hit the ball well, I controlled it and I made some putts. I knew my putting was right around the corner, I knew I was close because I hit good putts that just didn’t go in.
“It was just a matter of time, and this weekend was it.”
Woods effort has seen him improve 12 places to be the new world No 80
And Justin Thomas is celebrating in becoming the 21st different world No 1 and dethroning Dustin Johnson who has the led the rankings for 64 weeks