The veteran forward was on the substitutes' bench for the victory over Fiorentina last weekend after being out since October due to a hamstring injury, but he could make his eagerly-awaited return for the Eternal City club at San Siro.
Totti has played his part in training this week and despite suffering a blow to his calf that had threatened to extend his stay on the sidelines, the 37-year-old has shaken that off and is now nearing a return to full fitness.
His availability means that Adem Ljajic could make way, with Totti ready to reassume his role as the figurehead of Roma's title charge.
Rudi Garcia's side have struggled somewhat in his absence after a record-breaking start to the season, losing top spot in the table to Juventus - although they remain the only unbeaten side in Serie A.
Garcia is expected, though, to be without striker Marco Borriello (ankle), while midfielder Miralem Pjanic is suspended.
Milan head into the game as the only Italian side still in the UEFA Champions League after sealing their place in the last 16 by holding Ajax to a goalless draw in midweek.
Riccardo Montolivo's first-half red card did not prove to be costly as Massimiliano Allegri's side stood firm to secure the point they needed, in the process consigning the Amsterdam club to the UEFA Europa League.
Ninth-placed Milan are unbeaten in their last four Serie A games, but three of those have ended in a draw.
Defender Daniele Bonera is particularly wary of the the threat posed by the evergreen Totti.
"Totti is back and we always face clubs in certain situations. We need to be attentive and, from a sporting point of view, malicious," he told the Milan Channel.
"We need to be mentally in the game for 100 minutes. When we don't concede it's difficult that we draw.
"Wednesday (against Ajax) is an exception, but we were in a unique situation and one man down. When we're attentive we never concede."
Striker Stephan El Shaarawy will play no part after being ruled out for three weeks with a foot injury sustained early on against Ajax, as he made his first start since August.
