Hugo Lloris has started Tottenham's last five games after ousting Friedel from the first team, but the 41-year-old will have a chance to win back his spot on a permanent basis when he lines up against the Greek side.
Friedel's future at White Hart Lane has been in doubt since Tottenham rebuffed an enquiry from his former club Blackburn last month and should the Lancashire club bid for the player again in January, Villas-Boas says he will adopt the same stance.
"I don't know anything about (Blackburn's bid). We are trying to hold on to our best assets and Brad is certainly one of them," the Tottenham manager said. "Brad has been excellent, I spoke to him and he has been such an important player for us.
"Rotation has not been because of performances. Both goalkeepers' performances have been excellent. It gives me the ability at any time to throw a different keeper into the game. Hugo will not be involved in (the Panathinaikos) game."
If Friedel keeps a clean sheet then Tottenham will progress as they only need to draw to qualify for the knockout stages.
Unlike his predecessor, Harry Redknapp, Villas-Boas is a big fan of the Europa League as the competition proved to be the launch pad for his career when he won it with Porto in 2011.
The 35-year-old is therefore unhappy at Michel Platini's proposal that would see the Europa League scrapped in order to make room for an expansion of the Champions League.
"Increasing the Champions League means you have to remove the name 'Champions' out of it as it would not make any sense," he said. "I think it would be an unpopular decision, certainly for me it would be a disappointment."
Michael Dawson and Gareth Bale will miss thursday night's clash as they suffered hamstring injuries against Fulham but there was better news from the treatment room yesterday concerning long-term absentees Scott Parker and Benoit Assou-Ekotto, who are expected to be fit for next weekend's game against Swansea.