With both new coach Boris Becker and long-time adviser Marian Vajda on hand, Djokovic showed no signs of pain after withdrawing from last week's Madrid Open.
The second-ranked Serb's only trouble came as he attempted to close the match out, dropping his serve twice late in the second set before eventually finishing it off.
Djokovic, a two-time Rome champion, committed just nine unforced errors to Stepanek's 27.
It was a sharp contrast from Djokovic's last match, when he lost to Roger Federer in the Monte Carlo Masters semifinals last month, when he had his wrist heavily strapped and was unable to serve or return at his usual level.
In first-round women's play, Italian wild-card entry Camila Giorgi upset ninth-seeded Dominika Cibulkova 6-4, 7-6 (2) in a match delayed briefly due to rain, and 10th-seeded Sara Errani of Italy eliminated Chanelle Scheepers of South Africa 7-5, 6-3.
The 22-year-old Giorgi, who reached the round of 16 at the U.S. Open last year as a qualifier, showed off her attacking game, stepping into the court to whip winners into the corners at every opportunity.
Making her Rome main-draw debut, Giorgi had loud support on the picturesque Pietrangeli court, which is lined with neo-classical statues.
"The pressure is positive. It's great that the fans come to see you," Giorgi said. "Playing at home happens only once per year."
This tournament is the last key clay-court warmup before the French Open, which starts in two weeks.
Seven-time champion Rafael Nadal, Federer and women's title-holder Serena Williams open play Wednesday.