Her most acclaimed film role was in The Fisher King; her performance in the film earned her the 1991 Academy Award for Best Supporting Actress as well as an American Comedy Award, a Boston Society of Film Critics Award, a Los Angeles Film Critics Association Award, and a Golden Globe.
Ruehl is known for her leading performance in the play Lost in Yonkers (1990) and supporting performance in the film The Fisher King (1991). Her other film credits include Big (1988), Married to the Mob (1988), Last Action Hero (1993), Roseanna's Grave (1997), and Hustlers (2019). She also played the mother of main character Vincent Chase in HBO's Entourage.