Paulo Bento's side could only draw 1-1 with Israel on Friday, leaving them three points adrift of Group F leaders Russia, who have a far superior goal difference and travel to Azerbaijan on Tuesday.
A late blunder by goalkeeper by goalkeeper Rui Patricio cost the Portuguese as Eden Ben Basat grabbed a late equaliser at the Estadio Jose Alvalade.
Bento refused to point the finger at his keeper following the disappointment of the draw, but the Portugal coach will be expecting the Sporting Lisbon man to make amends for his costly error.
Portugal will be without captain Cristiano Ronaldo and his Real Madrid team-mate Pepe after they both picked up yellow cards against Israel.
Ronaldo denied picking up a caution for dissent on purpose in order to ensure he was not on a booking heading into the play-offs.
Even without two key players, Bento's charges will still be expected to get the better of Luxembourg in Coimbra and a comprehensive victory will give them confidence heading into the knock-out phase at the very least.
Portugal have qualified for each of the last three World Cup finals and they will still fancy their chances of boarding the plane to Brazil.
Luxembourg 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 last month and they will be determined to avoid finishing bottom of the group.
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