Zlatan Ibrahimovic is expected to start in the Milan attack, but Stefano Pioli is once again short of options at the back.
Milan-Spezia kicks off at 17.30 UK time at the Stadio Meazza.
Fikayo Tomori underwent knee surgery last week and will be out of action for a month.
Milan lost 43% of their matches without the former Chelsea defender (three out of seven) since the Englishman moved to the Meazza one year ago.
Sandro Tonali is suspended. Alessandro Plizzari, Simon Kjaer, Alessio Romagnoli, Pietro Pellegri, Fide Ballo-Toure, Franck Kessié and Ismael Bennacer are also not available.
However, Milan won two games from two, conceding once, in the opening two matches of 2022 with Pierre Kalulu and Matteo Gabbia in centre defence.
Theo Hernandez, Achraf Hakimi and Robin Gosens are the only defenders to have contributed to at least nine goals in the opening 21 Serie A games over the last 15 years, while the reverse fixture in October was the only match where Leao scored more than a goal in a single Serie A match.
Kevin Agudelo returns to action for Spezia but is likely to start on the bench. Thiago Motta can rely on full squad.
Spezia won the last two away games without conceding. They had won five of their previous 28, keeping just three clean sheets.
Probable line-ups
Milan (4-2-3-1): Maignan; Florenzi, Kalulu, Gabbia, Hernandez; Krunic, Bakayoko; Saelemaekers, Diaz, Leao; Ibrahimovic.
Spezia (4-4-1-1): Provedel; Amian, Erlic, Nikolaou, Reca; Kovalenko, Kiwior, Bastoni, Gyasi; Verde; Nzola.