The New Girl actress will return to the Fox animated comedy as Mary Spuckler, the hillbilly daughter of Cletus that Bart almost married in season 19.
Bart will reportedly track down a series of his past girlfriends in a plot similar to High Fidelity, reports Entertainment Weekly.
Anne Hathaway, Sarah Michelle Gellar and Sarah Silverman will also make cameos in the episode.
"It was a way to acknowledge that for a 10-year-old boy, Bart has gotten a lot of action," said The Simpsons writer and producer Tim Long.
"We thought it might be fun to borrow/pay homage to/steal an idea from High Fidelity and have him go on a romantic pilgrimage and visit the girls that he dated and try to figure out how the hell he screwed things up with each of them. I don't want to give away too much, but he realises that maybe there's something wrong with him after all."
Bart will visit his ex-girlfriends Gina (Gellar, season 15), Darcy (Portman, season 18), Jenny (Hathaway, season 20), and Nikki (Silverman, season 21), before finding out that Deschanel's Mary has moved to New York and deciding that he wants her back.
Long added: "Any resemblance between this episode and Breakfast at Tiffany's is completely coincidental."
'Moonshine River' will air on Fox in the upcoming 24th season, which will also feature Steve Carell and Jennifer Tilly.
Lady GaGa is set to appear in the season finale episode on May 20.