The Serie A leaders beat Celtic 3-1 in Glasgow in their opening Group H game. Sparta, however, had an opening night to forget as they were drubbed 4-1 at home by Ligue 1 high-flyers Lille.
First European goals from Rade Krunic and former Manchester City starlet Brahim Diaz preceded a late third from Norwegian forward Jens Petter Hauge, as Milan returned from their trip to the Scottish champions with maximum points last week.
Hauge, who played against the Rossoneri for Bodo/Glimt in the qualifying phase and subsequently signed for the club, tested positive for COVID-19 in the wake of that tie, but it was the positive result for dominant goalkeeper Gianluigi Donnarumma which has sent shockwaves through Italy.
Partly due to Donnarumma's absence, Milan were held at home by Roma in a 3-3 thriller on Monday, as their relentless winning run finally came to an end. His replacement, ex-Fiorentina stopper Ciprian Tatarusanu, appeared overwhelmed by the size of his task in replacing the Azzurri number one and made a number of disconcerting errors as the Giallorossi fought back to snatch a point.
Zlatan Ibrahimovic again bagged a brace, as he continues an apparently personal crusade to prove that age is just a number while dragging his side back to the summit of the Italian game.
Stefano Pioli fielded Ibrahimovic up front at Celtic Park but may be tempted to give the Swedish star a rest against Sparta as he endured a wearying 90 minutes against Roma just three days previously.
Otherwise, Pioli took the opportunity to field fringe players such as Hauge, Krunic and Diogo Dalot, on loan from Manchester United, and is likely to do the same throughout the group phase.
Thursday's opponents were reduced to 10 men midway through the first half against Lille, going on to equalise through skipper Borek Dockal before succumbing to numerical disadvantage after the break.
Ladislav Krejci was the man red-carded in that defeat, though he is one of a number of Sparta players that boasts Serie A experience, having had a four-year stay with Bologna which ended in the summer.
In addition, David Hancko is on loan to Sparta from Fiorentina and Ondrej Celustka had a brief stay at Palermo back in 2010, while striker Libor Kozak was the 2012-13 Europa League top scorer - with eight goals - during an otherwise barren spell at Lazio.
Sparta's already towering task in taking down Serie A giants Milan, however, was surely made insurmountable by the Czech government's declaration of a state of emergency due to the COVID-19 pandemic.
That has seen football in the country shut down entirely, with matches halted for a minimum of three league rounds. The visitors, therefore, have not played any domestic football since a win against Jablonec in early October and are left standing at the top of the table, with six wins from six.
Although this is now the club's 38th successive European campaign, Sparta have lost all of their last five European away fixtures and have just one victory in their last 10.
In stark contrast, Milan boast phenomenal recent form. This is the seven-time European champions' third appearance in the Europa League group stage - all of which have come in the last four seasons - and their home record in the competition is largely positive, with a record of eight wins from 11 games.
AC Milan Europa League form: W
AC Milan form (all competitions): WDWWWD
Sparta Prague Europa League form: L
Sparta Prague form (all competitions): WWWWWL
Diaz, Krunic and Dalot are all likely to return to the XI as Pioli refreshes his lineup after Monday's Serie A exertions.
AC Milan possible starting lineup:
Tatarasanu; Hernandez, Kjaer, Romagnoli, Dalot; Bennacer, Tonali; Krunic, Diaz, Castillejo; Leao
Sparta Prague possible starting lineup:
Heca; Hanousek, Lischka, Vitik, Sacek; Travnik, Pavelka; Vindheim, Dockal, Moberg Karlsson; Julis
We say: AC Milan 3-1 Sparta Prague
Whichever team Pioli names - even potentially without Donnarumma or Ibrahimovic - it is vanishingly improbable that this will be the day on which Milan's 26-game unbeaten run ends.
Rafael Leao is in scintillating form, creating and scoring goals at will, while the Rossoneri's supporting cast has more than enough ingenuity to pick apart an increasingly rusty and dispirited Sparta side.