Les Phoceens have lost all three of their matches in the Champions League group stage this campaign, while Rafa Benitez's men could go top with a win.
Rafa Benitez's side has won two of its three Champions League Group F encounters but sits third, behind group leaders Arsenal and Borussia Dortmund on goal difference.
In a match that could prove crucial in their hopes of reaching the round of 16, the Partenopei are heavy favorites to beat the struggling Phoceens.
The French side has lost all three of its Champions League fixtures and has slid to fifth in Ligue 1 after a dreadful run of form that has seen the club fail to win any of its last six matches in all competitions.
Napoli has not lost any of its five previous home games in the Champions League, winning four, and defeated Marseille 2-1 in France last month thanks to goals from Jose Callejon and Daniel Zapata.
Callejon has now scored eight goals in 12 appearances in Europe's premier club competition, with seven of them coming for former club Real Madrid.
Napoli has not lost a Serie A match at home in 2013, winning 14 of 16 encounters, and defeated Bologna 2-0 on Saturday.
Miguel Angel Britos (collarbone) and Camilo Zuniga (knee) are on the sidelines for Benitez's men.
Marseille ended a five-match losing streak at Rennes on Saturday but needed goalkeeper Steve Mandanda to save a late penalty to earn a 1-1 draw.
Jordan Ayew scored his first league goal since January in that clash, but the pressure on coach Elie Baup has not eased, with Marseille having won just twice since the start of September.
The club has kept just two clean sheets in the last two months and will need a miracle if it is to become just the second team ever to qualify from the group stages after losing its first three matches.
The feat was achieved by Newcastle United in the 2002-03 season but, in a group that also contains Arsenal and Borussia Dortmund, a repeat is unlikely.
Marseille will be without Lucas Mendes (ankle), while defender Rod Fanni (adductor) is unlikely to feature.