Amazingly both goalscorers were previously team-mates at English League One club Portsmouth as Kevin Prince Boateng and Sulley Muntari were on target.
Boateng fired home just before the hour before Muntari volleyed home a second with nine minutes left as Massimiliano Allegri's men took a huge win.
Milan looked willing to sit back and soak up Barca's attacks from the off, but it was their own counter attacking that showed the most threat throughout.
After 16 minutes Stephan El Shaarawy was sent clear into the box, but a heavy second touch gave Carles Puyol the chance to come across and put the ball behind.
From the resulting corner Boateng clipped the ball towards the back post and it only just landed wide of Victor Valdes' far post.
Xavi then tested Christian Abbiati with a sweetly struck shot from distance, whilst Pedro's somewhat weaker effort was also dealt with comfortably by the veteran keeper.
Lionel Messi began to enjoy spells of possession but, as Milan got numbers behind the ball, he was struggling to find space and, when he did, his team-mates could not do so.
El Shaarawy came close just before the break again, before the opener arrived 10 minutes into the second half, although there was an element of fortune about it.
Riccardo Montolivo's free-kick from 30-yards was blocked on the edge of the box, the ball span up and hit Cristian Zapata on the hand and it dropped into the path of Boateng, who fired into the corner. Barca protested but Scottish referee Craig Thomson waved away their complaints.
Barcelona looked for a reaction but nothing materialised. Alexis Sanchez was sent on for the ineffective Cesc Fabregas, but the Chilean added little spice to Barca's attacking play.
The unbelievably quiet Andres Iniesta flashed a volley wide whilst Xavi fired a free-kick over the bar and it was Milan who were to send shockwaves through European football as they made it 2-0 with just nine minutes remaining.
Substitute M'Baye Niang took the ball down and fed the excellent El Shaarawy, who in turn looked up and lobbed the ball over the Barca defence for Muntari to volley home from 10 yards and send the San Siro into raptures.