The former Ryder Cup player birdied the second extra hole with a 12-foot putt.
Both players had ended regulation play at 23-under par on the Old Course, with Howell shooting 5-under 67 and Uihlein a 69.
"To nail that birdie putt to win is pretty sweet," Howell said. "I was 0-5 in playoffs, so I felt as though I deserved one."
Howell beat Tiger Woods in 2006 to win the inaugural HSBC Champions event and has played more than 200 tournaments since his last victory in the BMW Championship later that year.
Howell began the final round two strokes behind Uihlein, but then burst into contention with five birdies in his opening seven holes, including four in succession starting at the fourth.
However, Howell played the back nine in even par while Uihlein, competing in the event for the first time, also stalled in completing his inward nine at 1 under.
Both players parred the first extra hole before Howell sealed a fifth European Tour victory.
"Hats off to David, (he) played great, made a nice birdie," Uihlein said. "He made more putts than I did at the end of the day."
Howell's win moves him back into the world's top 100 and also to 12th in the Race to Dubai, qualifying him for the European Tour's end-of-season final series for the first time in his career.
"It's a dream to be back in the big time, as it's been a long, long road from the depths of despair to get here today," Howell said.
Uihlein, who was looking to become the first American to win the tournament, moved to 10th on the Race to Dubai.