Paulo Fonseca takes bold action by dropping Rafael Leao and Theo Hernandez to the Milan bench, as Emerson Royal and Youssouf Fofana start against ambitious Lazio’s Taty Castellanos and Boulaye Dia.
It kicks off at the Stadio Olimpico at 19.45 UK time (18.45 GMT).
You can follow all the build-up and action from today’s four Serie A games on the LIVEBLOG.
The Rossoneri have had a disastrous start to life under Fonseca, scraping a 2-2 draw with Torino and well beaten by newly-promoted Parma.
The coach takes radical action, dropping Rafael Leao and Theo Hernandez, with summer signings Emerson Royal and Fofana getting their first starts.
Strahinja Pavlovic is also confirmed, especially as Malick Thiaw is out with an ankle problem, joining Alvaro Morata, Ismael Bennacer, Luka Jovic, Alessandro Florenzi and Marco Sportiello on the absentee list.
With so few strikers, Francesco Camarda and deadline day signing Tammy Abraham are on the bench.
Lazio are also a team in flux under a new coach, beating Venezia in the opener only to lose away to Udinese.
Luca Pellegrini joins Mario Gila on the treatment table, but Marco Baroni makes big changes, including ex-Salernitana pair Loum Tchaouna and Boulaye Dia stepping in, plus the first start for former Arsenal full-back Nuno Tavares.
The game is on Paramount+ in the USA. Fans in the UK and Ireland can watch it on TNT Sports 1 or OneFootball. beIN SPORTS 1 and streaming service beIN SPORTS CONNECT broadcast the Olimpico showdown live in Australia and New Zealand.
Lazio vs. Milan line-ups
Lazio: Provedel; Lazzari, Patric, Romagnoli, Tavares; Guendouzi, Rovella; Tchaouna, Dia, Zaccagni; Castellanos
Milan: Maignan; Emerson Royal, Tomori, Pavlovic, Terracciano; Reijnders, Fofana; Chukwueze, Loftus-Cheek, Pulisic; Okafor
