Standing 6-foot-10, Isner towered over the 5-foot-9 Sela and punished him with his serve.
The world number 12 cracked down 15 aces to end the run of the diminutive Sela who was playing his first ATP title for six years.
"This is my favorite time of year," American Isner told reporters.
“I'm off to a very good start again. I look forward to playing Washington D.C. again (this week). I've played well there my whole career." Isner’s familiar form helped him capture the opening set in 34 minutes as he won 14 of 15 points on his dominant first serve.
Trying to close out the match, Isner fell behind 30-0 in the final game but ripped off three straight aces to clinch the victory.
“Right from the very beginning I felt great,” Isner said. “These (hot) conditions favor me quite a bit. I couldn’t ask for better conditions.”
Isner was playing his fourth Atlanta final in five years. He was runner-up to Mardy Fish in 2010 and 2011 and won the title last year by defeating South African Kevin Anderson.
Isner is now 16-3 in his career at the Atlanta Open.
Sela said he had hoped to record a win for the people back home. A 20-day-old Israeli-Palestinian conflict in Gaza has claimed more than 1,000 lives.
“I wanted the win today for my people in Israel. It’s not easy the situation over there and hopefully it will be better,” Sela said.
“I tried to play for (that) theme but John was too tough for me today.”
The Atlanta tournament was the first in the U.S. Open series which offers a $1 million bonus at the U.S. Open for the player at the top of the standings.
(Reporting by Gene Cherry in Raleigh, North Carolina; additional reporting by Jahmal Corner in Los Angeles, Editing by Martyn Herman and Gene Cherry)