The midfielder, who made his name at Pompey before joining us in 1992, has failed to recover from the calf injury that forced him off early against Manchester United on Sunday.
Better news sees Bobby Zamora return after an Achilles problem that has kept him out for five games.
Paul Konchesky has been recalled by Charlton from his loan spell while both Stephen Kelly and John Jackson, recalled from loans at Watford and Coventry City respectively, are likely to be in the squad.
Acting boss David Pleat said: "We've lost Darren Anderton and we've lost Paul Konchesky from the last squad and the players still out are Simon Davies, Christian Ziege and Jamie Redknapp."
Darren Anderton will miss the Boxing Day encounter at his former club Portsmouth.