Milan need a point to be sure of the Scudetto and look to Rafael Leao, Rade Krunic and Olivier Giroud, but Sassuolo bring out the big guns including Domenico Berardi, Giacomo Raspadori and Gianluca Scamacca.
It kicks off at the Mapei Stadium in Reggio Emilia at 17.00 UK time (16.00 GMT).
Serie A Liveblog: Milan-Sassuolo, Inter-Samp, Salernitana-Udinese, Venezia-Cagliari
The Rossoneri have a superior head-to-head record with their city rivals, so a point would guarantee the title, although even a defeat would do if Inter fail to beat Sampdoria.
Simon Kjaer is the only injury absentee and Zlatan Ibrahimovic is on the bench, but Stefano Pioli sticks with his favoured XI including Krunic, Alexis Saelemaekers and Rafael Leao supporting Giroud.
Sassuolo have nothing more to play for, but want to end the season on a high, especially as it might be the last game for several of their stars.
It certainly will be for Francesco Magnanelli and Federico Peluso, but there are also big question marks over Berardi, Hamed Traore, Raspadori and Scamacca.
Davide Frattesi too has been heavily linked with a move to Inter.
Traore is left on the bench, replaced by Matheus Henrique in midfield for a 4-3-3 rather than 4-2-3-1.
There is a curious history between these clubs, as Sassuolo won the last two trips to San Siro and Milan the most recent two visits to the Mapei Stadium.
The Rossoneri lost their first three games on Sassuolo’s soil, then went on to win the next five in a row.
Sassuolo: Consigli; Muldur, Ayhan, Ferrari, Kyriakopoulos; Lopez, Frattesi, Henrique; Berardi, Scamacca, Raspadori
Milan: Maignan; Calabria, Kalulu, Tomori, Theo Hernandez; Tonali, Kessie; Saelemaekers, Krunic, Leao; Giroud