Simon, seeded second and ranked 25th in the world, had not reached an ATP semifinal in the United States before the Indianapolis tournament, which moved to a hard-court surface in 1988.
"That's special for me because it's not the kind of court I like to play usually," said the 23-year-old Simon, who earned his fourth career ATP title. "I beat some good players on this kind of court, that's why it's a very good thing to win this tournament."
Tursunov, seeded third and ranked 32nd, was hoping to join Pete Sampras and Andy Roddick as the only players to win back-to-back singles titles in Indianapolis since 1981. Tursunov beat Frank Dancevic in last year's final.
"To be honest, I didn't really feel that pressure," said Tursunov, who was seeking his fifth career ATP title. "I do get a bit of jitters and my game doesn't work that well when I'm nervous. I really have to go for my shots and there's very little margin for error."
Tursunov finished with 32 unforced errors, compared to 13 by Simon, and went 0-for-9 on break-point conversions.
"He played a few good points and then I made some silly errors," Tursunov said.
Simon said he didn't feel like the underdog, despite playing against the defending champion.
"Like every match I play, I think I can win," he said. "Even if I'm playing bad or good, I think I have a chance. ... I fight every time.
"Today was my best match of the week. I was very close to playing my best tennis."
Tursunov was impressed with Simon's performance.
"I've never played him before, so it's a bit surprising how many balls he can get to, and he moves really well around the court," Tursunov said.
Ashley Fisher and Tripp Phillips won the doubles championship with a 3-6, 6-3, 10-5 victory over Scott Lipsky and David Martin. It was the first doubles title in Indianapolis for both Fisher and Phillips.