Coach Filippo Inzaghi has been under pressure as Milan have stuttered their way through the campaign and occupy eighth place with nine games remaining.
At times during the season qualifying for Europe has looked highly unlikely, but Milan appeared to have turned the corner at just the right time while some of their rivals have slipped up.
Back-to-back wins prior to Sunday's clash have lifted the gloom, while also easing the pressure that was beginning to build on Inzaghi in what has been a baptism of fire for the former Milan striker.
However, he could end the season on a high after Juventus and Lazio qualified for the Coppa Italia final. With both sides already in European spots, sixth place could secure a UEFA Europa League place.
Napoli currently occupy sixth, but with Rafael Benitez's side in poor form a win for Milan could see them close to within three points.
Milan can expect a stern examination from Sinisa Mihajlovic's side, who currently sitting in fifth place after an impressive season under the Serb.
Last weekend's defeat to Fiorentina ended a run of four successive wins for the Genoa club and midfielder Djamel Mesbah knows the trip to Milan is key in their push for a top-five finish.
"If we win on Sunday we make a big step forward for Europe," he told the club's official website. "So let's focus on this challenge and play to win.
"But even after Milan, we will look to do that in every game.
"We are where we are, if we play like Sampdoria we can stay in the top five or six of the standings until the end."
Mihajlovic has been widely linked with a move at the end of the season, with Napoli reported interested in appointing him if Benitez leaves the club.
The former Lazio man will be determined to ensure speculation over his future does not affect his Samp side, who could yet secure a top-three finish.
Milan have been boosted by the return to training of Marco van Ginkel, Cristian Zapata, Cristian Zaccardo and Adil Rami, but Giacomo Bonaventura is a major doubt after suffering an ankle injury.
Samp have no new injury worries, but will have to do without defender Vasco Regini due to suspension.
