The title caps an impressive comeback for the Russian, who was competing in only his second tour-level event since his French Open quarterfinal run in May when he suffered a stress fracture in his back.
Khachanov, 27, dropped only one set en route to the final. It was his fifth tour title and first since Paris nearly five years ago.
The German recovered from being a set and a break down in the final to clinch a pivotal second-set tiebreaker against the 55th-ranked Russian, who was playing in his first career final.
Zverev, 26, broke Safiullin early in the decider before holding firm on serve for his second title of the year after winning at Hamburg in July.
At the Ningbo Open, third-seeded Sorana Cirstea defeated Claire Liu 7-5, 4-6, 6-3, while Kamilla Rakhimova beat sixth-seeded Arantxa Rus 3-6, 7-6 (5), 6-3 and Valeria Savinykh eliminated fifth-seeded Varvara Gracheva 7-5, 7-5.