Third-placed Inter are now eight points adrift of Milan with five games left after a shock 2-0 defeat at lowly Parma, meaning their hopes of a sixth straight scudetto are almost over.
Milan took the lead against beleaguered Samp through Clarence Seedorf on 20 minutes and striker Antonio Cassano sealed the win from the spot early in the second half after a contested handball before Robinho grabbed a third.
Milan were without suspended striker Zlatan Ibrahimovic but still left Samp, fourth last term, just a point above the drop zone.
Inter, dumped out of the Champions League as holders by Schalke in the quarter-final second leg in midweek, suffered a hangover at Parma who massively boosted their hopes of avoiding relegation.
On-loan Juventus duo Sebastian Giovinco and Amauri did the damage against old rivals Inter, whose only real hope of a trophy this term now lies with the Italian Cup with semi-final first legs being played next week.
Sixth-placed AS Roma, taken over by a U.S. consortium on Friday, suffered a late 3-2 home defeat by Palermo to hit their Champions League chances.
Uruguayan striker Abel Hernandez scored two late goals to steal victory.
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