Horschel topped the leaderboard at 14 under ahead of Bubba Watson after a run of 11 consecutive pars helped the American to a final-round 69 at Cherry Hills Country Club in Colorado.
While the 27-year-old was unable to replicate Saturday's seven-under-par 63, he still did enough to win his first PGA Tour title since April last year - the Zurich Classic of New Orleans.
More importantly, Horschel is now second in the FedEx Cup standings heading into the season-ending Tour Championship, having opened his campaign at the Cherry Hills Country Club in 20th position.
Compatriot Watson had a bogey-free back nine as he shot his third consecutive four-under-par 66 for sole possession of second spot.
Watson - the dual Masters champion - will head to Atlanta's East Lake Golf Club ranked third in the FedEx Cup standings.
Unheralded American Morgan Hoffmann was third at 11 under overall after he continued his scintillating end to the tournament.
After back-to-back 72s to start the tournament, the 25-year-old followed up his third-round 62 with a seven-under-par 63, which included an eagle and eight birdies.
American trio Jim Furyk (66), Rickie Fowler (68) and Ryan Palmer (67), and Spaniard Sergio Garcia (67) were five shots off the pace in a tie for fourth.
Palmer was second overnight but a capitulation on the back nine, that saw the American hole three bogeys and a double bogey, led to a fourth-place finish.
World number one and Northern Irishman Rory McIlroy (66) finished eighth alongside Australian Adam Scott (66) and American Jordan Spieth (67).
After four-putting his way to a triple bogey on Saturday, McIlroy four-putted for a double bogey at the same 12th hole.
McIlroy will be ranked fourth heading to the Tour Championship, while Scott rose to 12th - one spot behind Spieth.
Canadian Graham DeLaet closed the tournament in sole possession of 11th at seven under.
Meanwhile, American and Deutsche Bank Championship winner Chris Kirk is projected to top the FedEx Cup standings despite finishing 13 shots behind Horschel.