The skipper is suspended for the clash along with Real Madrid team-mate Pepe, with Paulo Bento's side knowing that victory would at least be enough to seal a play-off place
Paulo Bento's side could only draw 1-1 with Israel on Friday after Rui Patricio's error gifted Eden Ben Basat a late equaliser at the Estadio Jose Alvalade, leaving them three points adrift of group leaders Russia, who need only to avoid defeat in Azerbaijan to confirm their place at next summer's finals.
Portugal will be without captain Cristiano Ronaldo and his Real Madrid team-mate, Pepe, after they both picked up yellow cards against Israel.
The former denied picking up a caution for dissent on purpose in order to ensure that he was not on a booking ahead of the play-offs in November.
Even without two key players, Bento's charges will still be expected to get the better of Luxembourg in Coimbra as they look for the comprehensive victory which will keep alive their faint hopes of overhauling Russia on goal difference.
Ronaldo says that he is prepared for the "drama" of the play-off round, with Portugal having qualified for their last two major tournaments by virtue of a knock-out tie.
Luxembourg, meanwhile, were beaten 4-0 at home by Russia on Friday and are languishing at the bottom of the group with six points.
Portugal won 2-1 when the two sides met in September 2012, with Ronaldo and Helder Postiga on target after Daniel da Mota had given Luxembourg a shock lead.
The minnows have just one victory to their name in Group F against Northern Ireland in September and they will be determined to avoid finishing bottom of the group by securing a memorable result on Tuesday.