A Kevin-Prince Boateng blockbuster, a Robinho brace and a penalty from Zlatan Ibrahimovic gave the Italians their first win in seven Champions League clashes against English opposition while also ending a run of three straight home defeats against Premier League teams.
It means the second round, second leg at the Emirates in three weeks' time should be little more than a formality for Massimiliano Allegri's players.
Not even the introduction of Thierry Henry in his final appearance before returning to New York Red Bulls could inspire a surprisingly out of sorts Gunners formation.
And Arsenal manager Arsene Wenger didn't mince his words following Arsenal's worst ever defeat in Europe.
"We were never in the game, we were very poor both offensively and defensively," he said.
"It was shocking to see how we were beaten everywhere, it was the worst performance in Europe by far. There was not one moment during the 90 when we were really in the game."
Despite their advantage, Allegri remained cautious over his side's chances.
"We've not given a signal to other teams, we've got a good advantage over Arsenal and we have the possibility to get to the quarter-finals," he said.
"We did well tonight but we must still wait 90 minutes, it won't be easy because they'll have nothing to lose and will play a completely different match."
Any suggestions that Milan might have had an inferiority complex following their terrible run against the English were shattered in a first half in which the hosts were composed and clinical on the counter while the visitors were unsettled and error-prone.
A lovely move from Milan saw Luca Antonini chip the ball to Ibrahimovic who teed up Urby Emanuelson but the Dutch midfielder, on as an early substitute for Clarence Seedorf, couldn't match the neat build-up play with a comparable finish.
The hosts went ahead on the quarter hour mark when Arsenal goalkeeper Wojciech Szczesny scuffed a clearance straight to Antonio Nocerino who fed Boateng to crash a volley in off the underside of the bar.
Nocerino thrashed a volley over with Ibrahimovic screaming for a pass while the largely anonymous Robin Van Persie's free-kick was headed tamely by Laurent Koscielny into goalkeeper Christian Abbiati's arms.
Another Arsenal mistake saw Ibrahimovic, who was in tigerish form all night, sent scampering down the left on 38 minutes and he had time to pick out Robinho to head in from eight yards.
And it could have been worse at the break for the English side as Boateng shot into the side netting and Antonini poked wide having beaten Szczesny to the ball.
Arsene Wenger introduced Henry at half-time but any thoughts that might inspire the Londoners were dispelled within four minutes as more timid defending gave Robinho the time and space to shoot home into the bottom corner from the edge of the box.
Milan were ripping Arsenal apart on the counter and one such rapier attack with a three-on-two situation fell unfortunately to full-back Antonini whose finish was true to his occupation.
Arsenal finally put together a move of stunning quality on 65 minutes with Henry flicking the ball up for Van Persie to volley goalwards but Abbiati's save matched what had come before it.
And yet 11 minutes from time Ibrahimovic hammered the final nail into Arsenal's coffin as he used his wealth of experience to win a penalty in contact with Johan Djourou before putting away the spot-kick himself.
Abbiati would twice more deny Van Persie whose volley with his weaker right foot and header were both kept out.
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