Before starting her acting career, the Bronx native attended the prestigious High School of the Performing Arts in New York and studied drama and history at Hunter College. She continued to hone her acting skills in workshops at the renowned Actors Studio. Barkin made her professional acting debut in 1980, appearing in a theatrical production of Irish Coffee. In 1982, she starred in the original off-Broadway production of Extremities, with Susan Sarandon and James Russo. That same year, Barkin broke onto the big screen as the female lead in Barry Levinson's acclaimed comedic drama Diner, playing the vulnerable, neglected wife of an obsessive husband.