Milan are forced to revamp their defence, while Rafael Leao and Olivier Giroud lead the way against a Sampdoria side with Stefano Sensi and Francesco Caputo.
It kicks off at San Siro at 11.30 GMT.
Liveblog: Serie A Wk25 inc Milan-Sampdoria, Sassuolo-Roma, Atalanta-Juventus
After Napoli and Inter drew 1-1 on Saturday, Milan know a victory here would allow them to leapfrog both teams and go top of the table.
Their confidence is sky high after winning the Derby della Madonnina, then crushing Lazio 4-0 in the Coppa Italia midweek.
Zlatan Ibrahimovic, Matteo Gabbia and Simon Kjaer are still out of action, with Fode Ballo-Toure not at 100 per cent, while Theo Hernandez is suspended following his red card against Inter.
Fikayo Tomori is back in the starting XI after his injury, so Alessandro Florenzi is shifted over to left-back in order to plug the gap.
Franck Kessie is sent to the bench, with Ismael Bennacer partnering Sandro Tonali.
Giroud has four goals in his last two competitive games and leads the way with support from Brahim Diaz, Junior Messias and Rafael Leao.
Sampdoria are fresh off a 3-0 victory against Sassuolo and finding their feet under new coach Marco Giampaolo, who famously flopped badly on the Milan bench.
Manolo Gabbiadini has been ruled out for the season by a knee injury and new signing Sebastian Giovinco isn’t yet available.
Also on the treatment table are Mikkel Damsgaard, Maya Yoshida and Kristoffer Askildsen, so Ciccio Caputo starts upfront, with Inter-owned Sensi in support.
Milan: Maignan; Calabria, Tomori, Romagnoli, Florenzi; Tonali, Bennacer; Messias, Brahim Diaz, Leao; Giroud
Sampdoria: Falcone; Bereszynski, Colley, Magnani, Conti; Candreva, Rincon, Thorsby, Murru; Sensi; Caputo
That’s what I’m talking about. Keep Kessie on the bench please. No need for him.. At the same time, I wish he’s used for smaller teams (with all due respect) so that we save the others for the big ones.