The victory was the fourth in world number 57 Medvedev's five meetings with Johnson and far different than the last.
Johnson, ranked 34th globally, won that match in Eastbourne earlier this year in just 76 minutes and created eight break points. But Johnson struggled on Medvedev's serve this time.
The American entered the final having won 37 of 38 service games in the tournament. But Medvedev broke Johnson twice — once per set — to earn the victory.
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Ironically, the Russian had wondered in his first match how he would survive the North Carolina weather.
"It was so hot. It was so humid," he told ESPN. "I was like, 'How am I going to play six matches if I need to win the tournament?' So I thought okay, this is not my tournament.
"It's crazy," Medvedev said after winning it all.
His first career win had come in the Sydney International in January.
He will face compatriot Evgeny Donskoy in the first round of the U.S. Open.
Johnson was bidding to become the first player this year to win titles on three different surfaces. He claimed the U.S. Men's Clay Court in Houston in April and won the Hall of Fame event on grass at Newport, Rhode Island in July.
(Reporting by Gene Cherry in Raleigh, North Carolina; Editing by Ian Ransom)
