Three-time grand slam champion Wawrinka, whose most recent major success came at the 2016 US Open, was competing in just his second ATP Tour match in 14 months after recovering from a foot injury but battled past American Opelka 3-6 7-5 6-2 in Rome.
Opelka seemed to hold the initiative after dominating the first set and boasting a 4-2 advantage in the second, but the 37-year-old Swiss recovered well to fight back against the world number 17.
Wawrinka managed to release his heavy-hitting forehand and close the court by nearer to the net, with Opelka providing no response as the former world number three triumphed in two hours and five minutes.
Laslo Djere or Borna Coric will be the second-round opponent for Wawrinka, who registered his first tour-level win since February 2021.
Before defeating Opelka, Wawrinka had not won a match since he defeated Pedro Sousa at the Australian Open last season.
His only other ATP Tour match since then ended in defeat to Alexander Bublik in Monte Carlo last month.