Champions Inter now have an 11-point advantage over third-placed Milan with 14 games to go and lead Juventus by nine after Claudio Ranieri's side drew 1-1 at home to Sampdoria.
PHOTOS: Inter 2-1 Milan
Adriano broke the deadlock at an electric San Siro on 28 minutes when he diverted in Maicon's cross, but replays showed the Brazil striker had used his arm.
Midfielder Dejan Stankovic extended the lead on 42 minutes when he rifled in after Zlatan Ibrahimovic's knockdown.
The Serb had earlier been denied six metres out by a stunning last-ditch tackle by Massimo Ambrosini.
Alexandre Pato pulled one back 20 minutes from time when he tapped in Marek Jankulovski's cross and Milan then piled on the pressure with substitute Filippo Inzaghi being flagged offside when he thought he had grabbed an equaliser.
CONSTANTLY ISOLATED
Milan, who won the season's earlier derby 1-0, had much of the play in the first half but striker Pato was constantly isolated on his own up front with Kaka missing through injury.
Inter are bidding for their fourth straight scudetto and first under coach Jose Mourinho while Milan will have to pull off a miracle to snatch their first league title since 2004.
Media reports have said Milan coach Carlo Ancelotti, Serie A's longest serving manager having been appointed in 2001, could be sacked if they fail to win the league this term.
It was a sorry night for 40-year-old Paolo Maldini in his last derby before retiring while on-loan David Beckham, who still hopes to stay at Milan despite Los Angeles Galaxy demanding he return, did little and was substituted.
Juventus hit the woodwork three times against Sampdoria but had to be content with a draw. Giampaolo Pazzini put Samp ahead on 10 minutes after Antonio Cassano, constantly linked with a move to Juve, sent his strike partner clear with a superb through ball.
Amauri's brave diving header midway through the second half levelled the scores after a teasing cross from substitute Sebastian Giovinco.
Cassano's deflected cross struck the post for Samp.
Former Juve striker Adrian Mutu completed a hat-trick with the last kick to send Fiorentina up to fourth with a 3-3 draw at Genoa, who had led 3-0 but played with 10 men for an hour.
AS Roma's good run ended with a 3-0 defeat at Atalanta, who beat Inter 3-1 in Bergamo last month.
Roma, second last season before having a terrible start to the current campaign, had surged up the table after going undefeated in seven.
