The Argentina striker played the last 22 minutes of Friday's 2-0 defeat at Roma, having recovered from a hamstring injury.
Higuain had missed his team's previous two games, including the 2-0 reverse at Arsenal earlier this month.
Napoli head into the encounter at the Stade Velodrome, having seen their unbeaten run in Serie A ended by Roma.
Last week's result left the Naples outfit in second place, five points adrift of league leaders Roma, but top-scorer Marek Hamsik is confident his team will bounce back at the first opportunity.
"I am certain that we can react immediately," Hamsik said to Gazzetta dello Sport. "I didn't have a good game and we need to play better at Marseille than we did at Roma.
"We face a difficult game as Marseille are one of the best teams in the Ligue 1.
"But it's clear that if we want to progress to the next round we need to get a good result in France."
Napoli are third in the pool, level on three points with Borussia Dortmund and three points adrift of group leaders Arsenal.
The Italians will be without defender Miguel Britos and midfielder Juan Zuniga, both out injured.
Tuesday's match is even more important for Marseille.
The French side have lost their first two games in the competition - against Arsenal and at Dortmund - and another defeat would leave them with a mountain to climb to progress to the knock-out round.
Elie Baup's men go into the match on the back of a 1-0 defeat at Nice, that followed their 2-1 home reverse against Paris St Germain.
The outcome dropped OM to fifth in the standings, seven points behind Ligue 1 leaders PSG.
"Three consecutive defeats in all competitions is an indication that we are going through a difficult time," goalkeeper Steve Mandanda said to OmTV.
"Despite the loss and the fact that we conceded a goal, our performance against Nice wasn't bad.
"Obviously we are not happy but we remain united."
Baup expects an immediate reaction from his players.
"We have to turn our anger and frustration into determination against Napoli," Baup said. "I have not seen my players downbeat."
Baup will have Dimitri Payet available after the French midfielder missed the game against Nice through suspension.