The superstar is set to line out at Tallaght Stadium after shaking off a leg injury that nearly kept him out of the game.
The 38-year-old is the big name in Milan's 20-man travelling squad, which also includes new signing Sandro Tonali.
Tonali featured in a goalless draw between the Republic of Ireland and Italy Under-21s at Tallaght Stadium 11 months ago.
Goalkeeper Gianluigi Donnarumma, Danish defender Simon Kjaer, former Manchester City man Brahim Diaz and midfielder Franck Kessie will also travel to Dublin.
Milan boss Stefano Pioli said: “Our season begins with Shamrock Rovers. Unfortunately, we have one or two big absentees, but we need look at the positives that this can bring to the game. We know how tough these first matches can be: they’ve played more games and have more minutes in the legs. We’ll need to be alert for 90 minutes.”
While Milan will be the overwhelming favourites, club legend and current technical director Paolo Maldini has insisted they will not underestimate Rovers.
Maldini told Sky Italia: “We are ready, I hope. It’s a game that scares us a lot. It’s a team that is doing well, first in their league, we have some problems, Rebic disqualified, Leao injured. We play away from home in a knockout match, we are rightly worried.”