The Rossoneri are in search of their first away win of 2013-14 against the favored Blaugrana, who have lost once in their last 23 European home games.
The Catalan giant has made an excellent start to the season, topping La Liga with 11 wins from 12 fixtures, while also leading the way in Champions League Group H with seven points from three games.
New head coach Gerardo Martino has not lost a match since taking over at Barcelona - the club's last defeat came to Bayern Munich in May - and the team would move five points clear of Milan with a win on Wednesday.
Barca's recent form is in spite of a goal drought from Lionel Messi, who has scored just once, during the 1-1 draw at San Siro in last month’s reverse fixture with Milan, in his last five matches.
Messi has still scored four goals in three Champions League fixtures this term, with the Argentine netting a hat trick on matchday one against Ajax.
That was his fourth Champions League treble - a feat no other player has achieved - and his 24th hat trick for the Blaugrana.
Barcelona has lost just one of its last 23 Champions League fixtures at home - that being the 3-0 reverse against Bayern in last season's semifinals - while the team has won 21 in a row at home in La Liga.
While Messi has not been among the goals in recent times, Alexis Sanchez has helped to fill the void, netting five in as many matches.
Jonathan dos Santos suffered knee ligament damage last month and has been sidelined until next year, while Jordi Alba (hamstring), Ibrahim Afellay (thigh) and Isaac Cuenca (knee) are all long-term absentees.
Milan - which sits second in Group H with five points from three matches - has not won on its last five visits to Spain and suffered a 2-0 defeat to Fiorentina on Saturday, a result that saw the team slide to 11th in Serie A.
Massimiliano Allegri's side is already 19 points behind table topper Roma and a repeat of last season's third-placed finish looks unlikely, although the club also started poorly in 2012-13.
The Rossoneri have not won an away match this season, losing three and drawing four, and all signs point towards that trend continuing on Wednesday.
Defender Mattia De Sciglio (knee) made his first appearance since August last month, but attackers Stephan El Shaarawy (thigh) and Giampaolo Pazzini (knee) will be sidelined for some time.
Another defender, Daniele Bonera, is back in training following a knee injury, but is unlikely to feature in Spain.