In one of the standout fixtures in a stacked looking weekend of Serie A action, Milan's faultless start has them as slight favourites on their trip to the Italian capital.
Match preview
Mourinho is already under scrutiny after a poor start for Roma in his absence, as he has been serving a touchline ban following misdemeanours last season.
The Roma boss will hope the loan signing of Romelu Lukaku from Chelsea can improve their fortunes, especially with Tammy Abraham out long-term with a serious knee injury.
Despite two goals on the opening day, Andrea Belotti has never been to Mourinho's liking, so Lukaku will reunite with the manager who brought him to Manchester United back in 2017.
Many new faces have come through the door at Roma this summer, but Mourinho has been brutally honest in stating they are all players with a point to prove, as - in his words - no player who showed great form last season would have wanted to join the club.
Lukaku did show some promising signs in a largely frustrating season, starring late on in the Serie A campaign as Inter Milan secured Champions League football again, but his nightmare performance in the final still lingers in the memory.
For Houssem Aouar, Leandro Paredes, Renato Sanches and Sardar Azmoun though, all arrived out of form, with the latter two also currently out injured.
Mourinho needs a response from his side after picking up just one point from two winnable opening games this season.
Former Lazio man Antonio Candreva returned to the Stadio Olimpico and put on a dazzling display to earn Salernitana a 2-2 draw against the Giallorossi on the opening day.
Roma then slumped to a 2-1 defeat at the Bentegodi against Hellas Verona, with a woeful first-half performance turning out to be damaging.
Not since the 2011-12 season have Roma failed to win any of their first three league games, and they face a difficult task in avoiding repeating that feat.
That is due to AC Milan's fantastic start which has them top with a perfect record so far, and the league's best goal difference.
French duo Mike Maignan and Olivier Giroud played their part at either end of the pitch to earn Stefano Pioli's men a 2-0 win at Bologna to start the season.
New signing Christian Pulisic also scored on debut, and he netted another in a 4-1 thrashing of Torino last weekend.
The US international became just the fifth player in Milan's history to score in his first two league games for the club, as Giroud also converted two penalties in the rout to move top of the Serie A scoring rankings.
Milan, along with Napoli, Verona and Inter, are the four sides with maximum points, but the Rossoneri have looked the most impressive, given the manner of their successes.
Roma Serie A form:
AC Milan Serie A form:
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Team News
Roma will be without Paulo Dybala after their Argentine forward picked up a thigh problem at Verona last weekend.
Left wing-back Nicola Zalewski was concussed in the same match, and is expected to be unavailable, so Leonardo Spinazzola may make a return here.
Sanches has only played 26 minutes in a Roma shirt but is on the treatment table again to add to the frustrations he had at Paris Saint-Germain last season.
Azmoun arrived injured from Bayer Leverkusen, and joins Abraham and Marash Kumbulla, who are both out long term.
Lukaku has not had any match practice in pre-season after being castigated at Chelsea, so he is unlikely to be thrown in at the deep end from the start here.
Early form from Milan suggests Pioli will not change his side here, meaning Samuel Chukwueze, Noah Okafor and Yunus Musah will need to keep fighting for a spot in the side.
Ismael Bennacer is the only absentee, as the Algerian will be out with a knee problem until after the international break.
That injury paired with the departure of Sandro Tonali has not been felt though, thanks to the excellent form of recent arrivals Ruben Loftus-Cheek and Tijjani Reijnders in midfield.
Roma possible starting lineup:
Rui Patricio; Mancini, Smalling, Diego Llorente; Karsdorp, Pellegrini, Paredes, Aouar, Spinazzola; Belotti, El Shaarawy
AC Milan possible starting lineup:
Maignan; Calabria, Thiaw, Tomori, Hernandez; Loftus-Cheek, Krunic, Reijnders; Pulisic, Giroud, Rafael Leao
We say: Roma 1-2 AC Milan
Roma have found the net in 20 of their previous 21 home matches, while there have been three or more goals in nine of their last 10, and if they can get Lukaku on the pitch at any point, that will also heighten their goal threat.