After Milan made it through the playoffs and Slavia topped their group, the clubs' first-ever meeting takes place at San Siro.
Match preview
After slipping out of the Champions League by finishing third in this season's 'Group of Death', Milan overcame Rennes in last month's knockout-round playoffs upon their return to UEFA's second-tier competition.
A crushing first-leg victory set Stefano Pioli's side up to progress, and despite suffering a 3-2 defeat one week later, they ultimately finished the job in France, prevailing 5-3 on aggregate.
The Rossoneri therefore reached the Europa League's last-16 stage for the third time, but after failing to win a leg in either of their first two attempts - against Arsenal in 2018 and Manchester United three years later - they will expect to fare better on this occasion.
While Pioli has conceded that the Scudetto is out of reach, as his team trail city rivals Inter Milan by 16 points following a mixed run of results, pipping Juventus to second spot in Serie A and claiming some European silverware remain realistic targets.
Last year's Champions League semi-finalists are among the favourites to reach June's final in Dublin, with their attacking trio of Christian Pulisic, Rafael Leao and Olivier Giroud backed by an able supporting cast.
Alongside Giroud's deputy Luka Jovic, Swiss striker Noah Okafor has made some valuable cameos, and none more so than last Friday, when his late winner against a Lazio side that ended up with eight men stretched Milan's goalscoring sequence to some 23 matches.
Ahead of their trip to Lombardy, Slavia Prague have never won once in Italy despite eight previous attempts, of which they have lost seven - including a 2-0 reverse against Roma in this season's Europa League group stage.
However, the history books show that Slavia have only lost one first leg in their last 10 European knockout ties, while Jindrich Trpisovsky's current crop impressively finished first in Group G.
Winning five of six fixtures - that loss to Roma being the outlier - their 6-0 victory over Sheriff Tiraspol was the club's biggest in UEFA competition, outside of qualifying: they also became the first Czech team to top their group.
Another win over Sheriff was just Slavia's third in their last 10 European away games, though, and they now face a serious test of their credentials in Milan.
The Cervenobili warmed up for Thursday's contest with a goalless derby draw against Sparta Prague, who beat Trpisovsky's team to the title last term and also lead the Czech First League by four points from their old foes.
That stalemate followed Sparta's success in the clubs' cup quarter-final clash late last month, when Slavia were sunk in extra-time; therefore, they will arrive at San Siro seeking a first win in three.
AC Milan Europa League form:
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AC Milan form (all competitions):
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Slavia Prague Europa League form:
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Slavia Prague form (all competitions):
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Team News
Perhaps aiming to establish a healthy first-leg lead, as against Rennes, Milan boss Stefano Pioli is tipped to pick a strong starting XI on Thursday evening - the Rossoneri host Serie A strugglers Empoli this weekend.
Veteran defender Simon Kjaer could be rested, allowing Malick Thiaw or Fikayo Tomori to come into the hosts' back four, but few other changes are expected. Another centre-back, Mattia Caldara, recently returned to training after nearly a year out of action but is not fully fit.
Starting on the left side of an attacking triumvirate, Rafael Leao has scored three goals in his last four European appearances, netting in both legs of last month's playoffs - he had notched only three in his first 25 for the club.
After being sidelined since the winter break, Slavia goalkeeper Jindrich Stanek took his place between the posts for the 310th Prague derby, and he should start behind ex-Torino man David Zima and captain Jan Boril in the visitors' defence.
Christos Zafeiris and Ondrej Kolar are both ruled out by injury, but star striker Mojmir Chytil will be available to join fellow Czech international Vaclav Jurecka up front.
AC Milan possible starting lineup:
Maignan; Florenzi, Thiaw, Gabbia, Hernandez; Reijnders, Bennacer; Pulisic, Loftus-Cheek, Leao; Giroud
Slavia Prague possible starting lineup:
Stanek; Doudera, Holes, Zima, Vlcek, Boril; Jurecka, Masopust, Dorley, Schranz; Chytil