Milan hadn't beaten an English side in seven games since their 2007 triumph in the final against Liverpool but put that statistic to bed with a commanding performance against an Arsenal outfit who looked way out of their depth.
Former Tottenham midfielder Kevin-Prince Boateng slightly opened a wound for the Gunners before a double either side of half-time from Robinho and a late Zlatan Ibrahimovic penalty completely split things open as Max Allegri's men sent a message to the rest of the competiton.
After a vibrant start from Milan, the opening goal came just after the 15-minute mark in brilliant fashion when Boateng controlled Antonio Nocerino's chipped ball with his chest on the right side of the area before smashing a sweet volley over the head of Wojciech Szczesny and in off the underside of the crossbar.
In the 38th minute, Milan were two goals to the good when Ibrahimovic was somehow called onside but nevertheless he advanced deep into the Arsenal area before chipping back for Robinho from the byline who managed an improvised header from the edge of the six-yard box which found the back of the net leaving the visitors with plenty of work to do.
Less than four minutes into the second half, Milan went three ahead thanks to Robinho's second in about fifteen minutes. The Brazilian took advantage of Thomas Vermaelen's slip to take a first-time shot from the edge of the area from Ibrahimovic's pass which whizzed past Szczesny at his right post, sending the San Siro into raptures.
With just over 10 minutes remaining, Milan won a penalty when substitute Johan Djourou was adjudged to have brought down Ibrahimovic in the area with the Swede picking himself up to slot home to make it a goal in each of his five Champions League outings this season.
Earlier in proceedings, Clarence Seedorf lashed wide from outside the area but had to be subbed off for fellow Dutchman Urby Emanuelson in the 12th minute because of a hamstring problem just under 10 minutes before Nocerino was left unmarked at the top of the area but failed to get his well-struck shot on target as the ball just sailed over Szczesny's goal.
Late in the first half, after Arsenal's best defender Laurent Koscielny had to come off because of an injury, Boateng was cleverly played onside by Ibrahimovic but hammered his angled attempt into the side netting roughly 20 minutes before Arsenal's best effort which was cruelly denied by a great Christian Abbiati save when substitute Thierry Henry flicked on for van Persie who did well to strike his volley goalward.
In the 76th minute, van Persie had another awkward volley to hit, this time on his right foot, which Abbiati covered with ease before a very late header from the Dutchman was well-saved but the Gunners did nowhere near enough to trouble the AC Milan defence.
Arsene Wenger's Arsenal will now have plenty to do if they want to maintain their record of never having lost a knockout tie against an Italian club in the return leg on March 6 at the Emirates Stadium.
UEFA Champions League Round of 16 - first leg
San Siro, Milan - 60,000