Reus, struggling with a thigh issue, has been out since the defeat to Werder Bremen on penalties in the DFB-Pokal on February 5, while Piszczek has missed the last three games with a heel problem.
Dortmund’s season has threatened to derail in their absence, with three consecutive Bundesliga draws cutting their lead at the top to just three points, while Favre's men lost their Champions League last-16 first leg 3-0 at Tottenham.
And neither Reus nor Piszczek will be back to feature against Leverkusen at Signal Iduna Park.
"Both will not play on Sunday," Favre told a pre-match news conference.
Marius Wolf and Thomas Delaney are also doubts, having not trained with the rest of the team on Friday, but Manuel Akanji is close to full fitness.
Leverkusen are coached by former Dortmund boss Peter Bosz, with BVB sporting director Michael Zorc acknowledging: "When we play against Leverkusen, both clubs know each other very well.
"There are few secrets. This match will depend on which team performs their game the best."