The Swiss tennis player -- the second seed at the last major tune-up prior to the US Open -- defeated 122nd-ranked American teenager Jared Donaldson 2-6, 6-3, 6-4.
The match began Tuesday night but was held up several times due to rain before being postponed late in the evening. Wawrinka now plays Grigor Dimitrov, a winner over 16th seed Feliciano Lopez 5-7, 6-3, 7-6 (8/6).
Wawrinka set the pace for seeds on the first dry day of the week.
Olympic doubles gold medalist Rafael Nadal lived up to his third seeding in a defeat of Pablo Cuevas, 6-1, 7-6 (7/4) while there were victories for number four Milos Raonic and Japanese number five Kei Nishikori.
"I played a good match against a tough opponent in the first round for sure," Nadal said.
"After coming from Rio and after the marathon that I had in Rio, it's very important victory for me. So I'm very happy."
Raonic hammered a dozen aces, compared to 20 for losing opponent John Isner, as the Canadian beat the American for the first time, 7-6 (7/5), 7-6 (7/5). Nishikori stopped Russian Mikhail Youzhny 6-3, 6-2.
Jo-Wilfried Tsonga, seeded seventh, ousted American teenager Reilly Opelka 7-6 (7/5), 7-6 (7/3). Eighth seed Dominic Thiem won his first match since late June at Wimbledon, defeating Australian John Millman 7-5, 6-1.
Number nine Gael Monfils sent off Marcos Baghdatis 7-5, 6-0 and Australian Bernard Tomic upset 11th seed David Goffin 3-6, 7-5, 6-4.
Wawrinka's victory gives the two-time Grand Slam champion fresh motivation heading into the final third of the ATP campaign.
"I really want to qualify for London," Wawrinka said, referring to the eight-man World Tour Finals. "That's my main goal for the rest of the season.
"I have to stay inside the top eight," added the world number four, who is bidding for a fourth straight London appearance.
"I'm very happy to win this match. I had to get my bearings on court again."
In the women's draw, third seed and 2015 finalist Simona Halep started with a 6-3, 6-1 defeat of Annika Beck.
"I played pretty well today. I felt the game and the balls were a little bit heavier because of the rain and the humidity. But it was good for me," Halep said.
"I was a little bit nervous before the match because I had two weeks without matches. The first match of the tournament is tough. Now I'm more relaxed and I'm looking already forward to the next one."
Spanish fourth seed Garbine Muguruza won her first Cincinnati match with a defeat of CoCo Vandeweghe 7-6 (7/4), 6-2.
US Open finalist Roberta Vinci stopped Tsvetana Pironkova 7-5, 6-3. Hungarian Timea Babos upset Swiss 13th seed Belinda Bencic 7-5, 6-2. Bencic is still coming back from a wrist injury which forced her to quit a Wimbledon second-round match.
Spain's Carla Suarez Navarro won as Alize Cornet was unable to continue trailing 6-2, 1-0. British tenth seed Johanna Konta beat Donna Vekic 6-2, 6-3 and Barbora Strycova upset Australian 14th seed Samantha Stosur 7-6 (13/11), 6-3.