The Dutchman won La Liga with Barca in 1999 but now needs to find a way to topple them in Europe's premier competition.
Barcelona are already through to the knockout stages and sit five points clear at the top of Group H, with Ajax third on four.
With AC Milan second on five, a defeat for Ajax and a Milan win over Celtic would leave the Europa League as De Boer's best remaining option.
De Boer is hoping, though, that salvation can come in the form of Lionel Messi missing out for Barca through injury.
Messi scored a hat-trick in a 4-0 win when the sides met in September.
"We would like to be second," De Boer said at the pre-match media conference.
"And of course it makes a difference whether Messi plays or not. He scores lots of important goals and gets assists.
"On the other hand, Barcelona have not lost many points without Messi. They have many good players and are a nice team. We must arm ourselves as well as we can.
"Normally Barcelona have more quality but the best team does not always win."
The omens are not good for Ajax considering they have lost their last nine matches against Spanish opposition, although they will be in good spirits after their 3-0 victory over Heracles on Saturday.
But although qualification is already safe, Barca's sporting director, Andoni Zubizarreta, insists there will be no let up in Amsterdam.
"We are travelling with the intention of securing the top spot and continuing with a phase that has gone very well so far," he said at a media conference.
"Our aim is to win every game. We want to compete with a historic team like Ajax at a historic venue. This is a top-level Champions League match and we have to be up to the occasion".
The demanded intensity may be hard to find with a weakened side, though.
Aside from Messi, keeper Victor Valdes is injured, with in-form Alexis Sanchez suspended.
Dani Alves (calf) and Jordi Alba (hamstring) are also unlikely to be fit for Barca's 250th game in the Champions League.