Ron Rifkin received a 1998 Tony Award for Best Supporting Actor for the Broadway revival of Cabaret. His other theatre credits include David Hirson's Wrong Mountain, Arthur Miller's Broken Glass, Turgenev's A Month in the Country and Neil Simon's Proposals. Rifkin originated the role of Isaac Geldhart in the Jon Robin Baitz play, Substance of Fire, in which he won the Obie, Drama Desk, Lucille Lortel and Drama-Logue Awards for Best Actor. The following year he performed in Baitz's Three Hotels, for which he received a second Lucille Lortel Award and Drama Desk nomination. He also appeared in Light Up the Sky at the Williamstown Theatre Festival. During the summer of 2002, Rifkin reunited with Baitz in a production of Ten Unknowns at Boston's Huntington Theatre. In the winter of 2004, he once again reunited with Baitz to star in his play, The Paris Letter, at the Kirk Douglas Theatre in Los Angeles, which was followed by a production in the summer of 2005 at the Laura Pels Theatre in New York.

Rifkin's film credits include The Sum of All Fears, Dragonfly, The Majestic, Boiler Room, Keeping the Faith, The Negotiator, L.A. Confidential, the film adaptation of Substance of Fire, Woody Allen's Husbands and Wives and Manhattan Murder Mystery, Last Summer in the Hamptons, Wolf, JFK, The Sting II, The Big Fix, The Sunshine Boys and Silent Running.

On television he has appeared in numerous made-for-television movies and miniseries, including Flowers for Algernon, Norma Jean and Marilyn, The Sunset Gang, Concealed Enemies, Buying a Landslide, Evergreen, The Winds of War and Dress Gray. He was also seen in the television film Deliberate Intent, opposite Timothy Hutton, and appeared in several episodes of Nero Wolfe, with Hutton directing. He starred in the series Alias, One Day at a Time and The Trials of Rosie O'Neill, and guest starred on Sex and the City, ER, Law & Order, Falcon Crest, Soap, Hill Street Blues and The Outer Limits.