The Rossoneri went ahead early thanks to Adel Taarabt, then fellow loanee Adil Rami doubled the lead before Maxi Lopez was sent off for the Blucerchiati.
Adel Taarabt, who joined on loan from Championship outfit QPR during the January transfer window, scored the first goal of the game 12 minutes in and helped to create the second as the Rossoneri won at Sampdoria in the league for the first time since October 2007.
Taarabt opened the scoring early in the first half, poking home at the second attempt after being picked out by Adil Rami's right-wing cross.
The roles were reversed just before the hour mark, Taarabt's delivery eventually finding the Frenchman to nod home at the back post after Giampaolo Pazzini had challenged goalkeeper Angelo Da Costa for the ball.
Sampdoria substitute Maxi Lopez was dismissed 20 minutes from time, the Argentine picking up two bookings for dissent in quick succession to compound a miserable day for the hosts.
The result continues Milan's recent resurgence, with the San Siro outfit having now taken 13 points from Clarence Seedorf's six league games in charge.
Blucerchiati coach Sinisa Mihajlovic called on his side to show an improved attitude before the game, but in truth it showed little attacking threat as it fell to a first home defeat under the Serbian.
Milan had nine changes from its Champions League defeat midweek: Mario Balotelli and Mattia De Sciglio were absent through injury while goalkeeper Christian Abbiati missed out with illness, with Marco Amelia coming in.
However, it was the two men who kept their place from Wednesday's defeat that combined for the opening goal in the 12th minute.
Taarabt and Pazzini had already threatened for the visitors before Rami picked out the Moroccan from the right and, although he saw his free header saved by Da Costa, the playmaker reacted quickest to prod home his second goal since moving to Serie A in January.
Samp made a brighter start to the second period, but Rami doubled Milan's advantage in controversial circumstances in the 58th minute. As Taarabt crossed from the right, Pazzini challenged Da Costa for the aerial ball and with the keeper flattened, Rami was able to nod home into the unguarded goal.
Lopez, introduced 15 minutes earlier, saw red in the 72nd minute as Samp's frustrations boiled over. The result leaves Milan five points behind rival Inter for the final Europa League qualifying spot as Seedorf and his men look to salvage something from a turbulent season.