Djokovic is returning after three weeks off due to a lingering issue with his surgically repaired right elbow.
In his previous two tournaments on red clay, Djokovic had consecutive early exits.
He lost in the round of 16 at Monte Carlo to Lorenzo Musetti. Then Dusan Lajovic beat him in the quarterfinals of the Srpska Open in Bosnia and Herzegovina, dealing him his first loss to a countryman in 11 years.
"It's all good," Djokovic said of his elbow. "I mean, there's always some things here and there that bother you on this level. It's normal.
"Also when you're not 25 anymore, I guess you experience that a bit more than what used to be the case," added Djokovic, who will turn 36 the day after this tournament ends. "It takes a little bit more time to recover."
Djokovic, who won the Australian Open at the start of the year, is clearly aiming to peak around the Grand Slams.
After a first-round bye, he'll open with a night match Friday against Tomas Martin Etcheverry, an Argentine who reached clay finals in Santiago, Chile, and Houston earlier this year.
No matter his results at the Foro Italico, Djokovic will cede the No. 1 ranking back to Carlos Alcaraz after this tournament.
Alcaraz, who is making his Rome debut, is seeded second and in the opposite side of the draw from Djokovic.
While they have been trading the top spot back and forth, it's the first time this year that both Djokovic and Alcaraz have entered the same tournament.