The True Blood actress, who appeared in Marvel's short film Item 47, said that she is unlikely to reprise her role for the Avengers tie-in due to other commitments.
"I have my own show so I will not be a regular on the Marvel S.H.I.E.L.D. show. But I'm glad people are so excited about that. I think it's a good idea... Maybe I could do some little thing," she told Super Hero Hype.
Caplan is due to appear in Showtime's Masters of Sex alongside Michael Sheen and Caitlin Fitzgerald, which will begin a 12-episode run next year.
Whedon previously confirmed that S.H.I.E.L.D. will centre on new characters, rather than use existing ones from the Marvel film universe.
Production on S.H.I.E.L.D. is about to commence, but an air date is yet to be announced.