The two clubs have never previously met in European competition, and their first competitive encounter comes after the German champions coasted to victory on the opening matchday and Milan were well beaten at San Siro.
Match preview
Following last season's record-breaking feats, Bayer Leverkusen had plenty to live up to when making their Champions League comeback, and the ruthless nature of an emphatic 4-0 win away to Feyenoord suggests they can also make a big impact this term.
Florian Wirtz became the first German player to score twice on his Champions League debut, as Leverkusen recorded their biggest away victory in the competition to date.
Having stylishly kicked off their quest to reach the knockout rounds for the first time in eight years, Die Werkself could now win their opening two matches for the first time since 2001 - a season in which they went on to lose against Real Madrid in the final.
The German champions come into Tuesday's game unbeaten in their last nine home matches in UEFA competition - they have never previously gone 10 in a row without defeat - and having won five of six home fixtures en route to last season's Europa League final.
Overall, Leverkusen have lost just two of their last 21 continental contests, though incidentally both were against Italian opposition - Roma and their only conquerors last term, Atalanta BC.
Since cruising to victory at De Kuip, the Bundesliga side edged a seven-goal thriller with Wolfsburg in typical last-gasp style, before ending Bayern Munich's 100% start to the season with a 1-1 draw in Munich.
However, they have now shipped 10 goals in their first five league games, so head coach Xabi Alonso - who scored Liverpool's third goal in the 2005 Champions League final against Milan - will be keen to tighten things up at the back.
Of course, Milan then had their revenge over Liverpool in the 2007 decider, and the two European giants convened again on this year's opening matchday.
Never able to live with their Premier League opponents, the hosts conceded 11 shots on target at San Siro - their joint-most on record in a Champions League fixture - and ultimately succumbed to a 3-1 defeat.
Milan have now won only nine of their last 32 games at the elite level, despite making it through to the 2023 semi-finals, and last year's win at Newcastle United was just their fourth in 17 away from home.
Nevertheless, back-to-back league wins in less than a week have breathed new life into a squad seemingly ailing under new coach Paulo Fonseca, who was already facing talk of being sacked within weeks of his appointment.
After six derby defeats in a row, the Rossoneri finally toppled arch-rivals Inter Milan, with boyhood fan Matteo Gabbia heroically heading home the late goal that secured a long-awaited 2-1 win.
Then, having tasted success in the season's first Derby della Madonnina, Fonseca's side swept aside Lecce on Friday night, when first-half strikes from Alvaro Morata, Theo Hernandez and Christian Pulisic secured a 3-0 home victory that took them second in Serie A.
The seven-time European champions therefore have hope of upsetting Xabi Alonso's well-oiled machine in midweek, as they aim to win their first away fixture for just a second time in eight Champions League campaigns.
Bayer Leverkusen Champions League form:
W
Bayer Leverkusen form (all competitions):
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L
W
W
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D
AC Milan Champions League form:
L
AC Milan form (all competitions):
L
D
W
L
W
W
Team News
Bayer Leverkusen made five changes for their high-profile clash with Bayern at the weekend, but Xabi Alonso is likely to retain most of that starting XI against Milan.
Captain Granit Xhaka is certain to feature in midfield, but Robert Andrich - who scored Die Werkself's goal on Saturday - must compete with Aleix Garcia and Exequiel Palacios to partner him.
Also an automatic first-choice selection, Florian Wirtz has been directly involved in 24 goals in his last 26 European starts and had scored four times in three games before firing a blank in Bavaria.
Meanwhile, Milan's main threat may come from a former Germany-based player enjoying some scintillating Serie A form this season. Christian Pulisic has found the net in his last four matches - all four goals coming during the first half - and will now try to become the first man from the United States to score in three consecutive Champions League appearances.
Tammy Abraham has recently joined Pulisic, Rafael Leao and Alvaro Morata in the Rossoneri's attack, but Ruben Loftus-Cheek could come back in to add more midfield cover against top-class opponents.
Marco Sportiello (hand), Ismael Bennacer (ankle) and Alessandro Florenzi (ACL) are all sidelined by injury, while captain Davide Calabria is struggling with a muscular problem.
Bayer Leverkusen possible starting lineup:
Hradecky; Tapsoba, Tah, Hincapie; Frimpong, Andrich, Xhaka, Grimaldo; Terrier, Wirtz; Boniface
AC Milan possible starting lineup:
Maignan; Emerson, Tomori, Gabbia, Hernandez; Fofana, Reijnders; Pulisic, Loftus-Cheek, Leao; Abraham
We say: Bayer Leverkusen 2-1 AC Milan
While Leverkusen have only failed to score in two of their last 60 matches, Milan's defence is dubious and can be caught out by teams with sufficient quality to punish them.