The pair will appear in several episodes of the TV Land sitcom towards the end of May, according to The Hollywood Reporter.
O'Donnell will play Katie O'Grady, an old school friend of main character Fran (Fran Drescher) and Judi (Tichina Arnold). She arrives to help Fran with her relationship with her difficult mother Dori (Rita Moreno).
Aykroyd will appear as a potential love interest for Fran, after her ex Peter (John Michael Higgins) sets them up.
Happily Divorced is now airing its second season after being renewed last year.
Aykroyd is currently working on a third Ghostbusters film, which is said to be in "suspended animation" since Bill Murray dropped out.
He recently announced that he has reunited with his Spies Like Us co-star Chevy Chase on a new project.