Segel revealed in March that he'd love Clinton to follow in the footsteps of his on-screen romantic interests Kristen Bell, Mila Kunis and Emily Blunt because he felt the politician would be "good at comedy".
Clinton apparently sent Segel a written response to his request, in which the US Secretary of State teased that she is too busy for any film projects.
"I was delighted to read about your interest in sharing the big screen with me," Clinton wrote, reports Politico. "As you can imagine, I am a little occupied at the moment, but perhaps someday I can help you forget Sarah Marshall… again."
Clinton added humorously: "My only condition is there be Muppets involved, and that is non-negotiable. In the meantime, you have my best wishes for continued success with your career."
Segel first revealed he'd received a "rejection letter" from Clinton while appearing on Late Night with Jimmy Fallon last week.
He is currently starring in The Five-Year Engagement, which is now playing in the US and opens in the UK on June 22.
Watch a trailer for The Five-Year Engagement below: