Both sides have endured inconsistent starts to the 2013-14 campaign but a win on Wednesday could reignite their hopes for a top-three finish.
Wednesday's clash will give two of Italy's biggest sides a chance to revive their season after making slow starts.
Lazio – which last won a league game against Milan at the venue in September 1989 thanks to Paolo Maldini's own goal - has struggled recently, winning just one of its last six matches in all competitions.
After winning three of its first five Serie A fixtures, the club has fallen to seventh in the table, with a lack of goals a concern for head coach Vladimir Petkovic.
The Rome club has scored 14 goals in nine matches this season – only one side in the top half of the table has scored less – with only midfielder Antonio Candreva having netted more than two league goals, with a total of four strikes.
Lazio winger Senad Lulic (thigh) will not feature in the clash, while defenders Andre Dias (knee) and Vinicius (hamstring) will also miss out.
Milan will be hopeful a return to San Siro inspires the team to victory after it fell to 10th in the table following a 3-2 defeat at Parma on Sunday.
Massimiliano Allegri's side is already 16 points adrift of table-topper Roma and, despite the season still being in the opening quarter, a 19th Scudetto looks beyond the team.
The club's abysmal away form is largely to blame, with Sunday's loss just the latest in a string of disappointing results on the road.
Milan has won none of its five away matches this season, losing three and drawing two, while the team has conceded 13 goals in the process.
"We keep making the same mistakes away from home," Allegri bemoaned after the loss to Parma. "Mario Balotelli had a bad game. Now our race to get back near the top is getting tougher."
Milan can take some comfort in its home form, having won three of their four matches at San Siro this season, but the team needs more from its strikers.
Balotelli, Robinho and Alessandro Matri have scored a combined total of just six goals for a side who are badly missing young star Stephan El Shaarawy (foot) and Giampaolo Pazzini (knee).
Defenders Philippe Mexes (suspension), Daniele Bonera (knee) and Matias Silvestre (calf) will also miss the match.
This fixture has not been won by an away side in the last seven meetings, with Milan winning the most recent encounter 3-0 in March thanks to a Pazzini double.