Kizzire closed with rounds of 66-67 for a one-shot victory over Fowler, who fell four shots behind at El Camaleon Golf Club until he staged a late rally that again fell short. Fowler had rounds of 67-67 on the final day.
Kizzire won in his 62nd career start on the PGA Tour, and it required some steady nerves on the back nine, when it could have gotten away from him. Leading by four shots with seven holes to play, Kizzire saved par with an 8-foot putt on No. 12, a 10-foot putt on the par-5 13th and an 8-foot putt on the 14th.
He had a three-shot lead with three holes to play when Fowler made a 15-foot birdie putt on the 16th hole and rolled in a 12-foot birdie putt on the 17th hole to close within one shot. From the 18th fairway, Fowler sent his approach some 35 feet left of the flag and left the birdie attempt short.
Kizzire had to stand close to his approach shot to keep his feet out of the sand, and he hit an 8-iron to 25 feet. After Fowler left his birdie attempt well short, Kizzire rapped his putt to within a few inches and tapped in for the winning par.
"I was glad to get it done," Kizzire said. "Rickie made me work hard."
Kizzire finished at 19-under 265 and earned his first trip to the Masters in April. The 31-year-old Kizzire also gets a two-year exemption on the PGA Tour and a spot in the field at the Sentry Tournament of Champions at Kapalua to start next year and the PGA Championship, along with other select events on tour.
Si Woo Kim tried to get into the mix until a double-bogey in the middle of his back nine. He closed with a 65 to finish third, his best finish since he won The Players Championship in May. Charles Howell III (66) and Martin Piller (65) finished five shots behind. John Oda of UNLV, playing his first PGA Tour event as a pro, closed with a 70 to finish eighth. That gets him into the RSM Classic next week at Sea Island.
Patrick Rodgers began Sunday in a three-way tie for the lead with Kizzire and Fowler, but he started and ended the third round Sunday morning with a double-bogey for a 72 that took him out of contention, and he shot 70 in the afternoon to finish nine shots behind.
Kizzire won the tournament with key putts on the back nine, but the tournament turned in his favor at the end of the third round. Fowler had a one-shot lead when he made bogey on the 17th hole and Kizzire made birdie. That two-shot swing gave Kizzire a one-shot lead, and he quickly expanded it in the fourth round.
Kizzire saved par with a 10-foot putt on No. 1 as Fowler made bogey, and then Kizzire birdied the second hole, and his lead was already at three shots. Fowler never got any closer until the final few holes, and by then it was too late.
"We gave it a run, kept Patton honest, but he earned it out there today," Fowler said.
Fowler, the only player in the top 10 who played anywhere in the world this week, was playing for the first time since the Presidents Cup five weeks ago. With his runner-up finish -- the 12th time in his PGA Tour career that he has finished second -- Fowler moves to No. 7 in the world ahead of Rory McIlroy.