The Portuguese giants are three points behind second-placed Olympiacos with two matches remaining in Group C after being beaten 1-0 by the Greek champions in the last round of games.
Jorge Jesus' side are six points adrift of leaders Paris Saint-Germain, who only need a point to secure their place in the knockout stage when they host Olympiacos on Wednesday.
Jesus is currently serving a 30-day domestic suspension after an altercation with police on the pitch after his side's victory at Vitoria Guimaeres in September.
However, that ban does not apply to European competition so the Benfica coach will be on the touchline at the Constant Vanden Stock Stadium.
The Lisbon outfit made a great start to their Champions League campaign when they beat Anderlecht 2-0 in their first game back in September, but they have only picked up one point from the three games since then.
Olympiacos consigned Benfica to a 1-0 defeat in their last group game earlier this month and they can ill afford to slip-up again.
Benfica come into the game on the back of a 1-0 win over Braga on Saturday and they are third in the Primeira Liga, just a point behind leaders Porto.
Anderlecht need to win both of the last two group games to have any chance of progressing to the knockout stages and even then they would leave them reliant on other results going their way.
The Belgian champions are bottom of the group but they claimed a surprise draw at PSG in their last European encounter to get up and running.
John van den Brom's side conceded 10 goals and failed to score in their first three games, including a 5-0 home thrashing against a Zlatan Ibrahimovic-inspired PSG.
Demy de Zeeuw gave Anderlecht a shock lead at the Parc des Princes, but Ibrahimovic denied them a stunning win with an equaliser two minutes later.
The Belgian outfit were beaten 2-1 at Charleroi at the weekend and they are down in fifth place in the Pro League.
