Isner fired 15 aces and broke Sela twice in the 71-minute encounter, remaining unbeaten in three career contests with Sela.
Isner nabbed his ninth ATP title and a second Atlanta crown. His triumph over South African Kevin Anderson in last year's title match came after runner-up finishes to Mardy Fish in 2010 and 2011.
But the world number 12 had to fight his way through this week. In his opening match against fellow American Robby Ginepri Isner fought off two match points en route to a 4-6, 7-6 (7/5), 7-5 win.
Sunday’s victory gave Isner the lead in the US Open Series bonus challenge standings. The top three finishers will vie for up to $1 million in bonus prize money at the US Open, the final Grand Slam of the year that starts in Flushing Meadows next month.
"This is my favorite time of year," Isner said of the hardcourt season in his homeland.
"I'm off to a very good start again. I look forward to playing Washington DC again. I've played well there my whole career."
Sela had advanced to his first ATP World Tour final in almost six years, defeating ninth-seeded Sam Querrey and fourth-seeded Vasek Pospisil en route to the title match.
He lost in the 2008 Beijing final to now-retired Andy Roddick.