Smith completed his second win of the season at the 16-under-par 264.
Third-round leader Gillespie shot a 5-under 65 Sunday to end alone in second at minus-15. Lee Curry was two strokes further after a final-round 66.
Smith opened with a birdie on the first, then connected on back-to-back birdie chances from the fifth to move to 12 under. He parred seven in a row from there.
The 26 year old ran off four straight birdies from the 14th at Lakeview Golf Club to take the lead and he closed with a par for the win.
Smith lost last week to Brent Schwarzrock, who closed with a 62 in the final before winning the title in a playoff.
'That was hard-fought, especially after that heartbreaker last week,' Smith stated. 'These guys weren't going to give me anything. I had to work for it.'
Gillespie birdied the 17th, but needed another at 18 to force a playoff. He found the rough off the tee and didn't give himself a chance at birdie.
'He just played better golf,' said Gillespie, who posted his fifth top-five of the year. 'Anytime you are leading and shoot 65, it should be enough. But the same thing happened to Byron last week when Schwarzrock beat him. This week he was that guy.'
Ryan Horn took fourth at 9-under-par 271 after a closing 68. James Lepp and Mike Grob were one stroke back at minus-8.
Tom Stankowski and Wes Heffernan shared seventh while Kevin Kisner, Graham DeLaet and Adam Speirs tied for ninth at minus-6.