The actress notably appeared in the lead role in The Avengers tie-in short film Item 47 as part of a duo of bank robbers who are invited to join S.H.I.E.LD.
Caplan has now told Entertainment Weekly that her commitment to Showtime's Masters of Sex won't allow her to appear regularly on Marvel's new series.
"I know they're making that S.H.I.E.L.D. TV show. I think that would be the natural trajectory for where my character ends up. But I'm doing another television show so I can't be on that one," she explained.
Caplan went on to say: "I like all those guys at Marvel quite a bit, and I'd love to work with them again. But as of now, I can't do their show and I think that's the next thing they seem to be focusing on."
S.H.I.E.L.D. is to feature Ming-Na Wen, Iain De Caestecker, Elizabeth Henstridge and Brett Dalton as agents of the espionage organisation.
Clark Gregg is also expected to appear in the S.H.I.E.L.D. pilot as Agent Phil Coulson, despite the character's demise in The Avengers.