McGillis dropped out of high school to pursue a career as an actor and eventually attended Juilliard in Manhattan. She understudied the role of Dona Elvire in a New York Shakespeare Festival production of "Don Juan" but had little other professional experience when director Robert Ellis Miller "discovered" her and cast her opposite Tom Conti in "Reuben, Reuben". Notices were good, and McGillis then moved to "Witness" and "Top Gun." (In the latter, her 5'10" height was quite evident as she stood next to the shorter Tom Cruise.) Attempts to put her in the position to carry a picture resulted in "Made in Heaven" (1986), in which McGillis was matched with Timothy Hutton as the as-yet-unborn beauty he meets in heaven, who is yet unborn, and "The House on Carroll Street" (1988), in which McGillis was a blacklisting victim who stumbles on an espionage plot. Both films were box office disappointments. "The Accused" (1988) had McGillis as the assistant district attorney who is moved to put three rapists behind bars by the pathos of Jodie Foster, but it was Foster who got the reviews--and the Oscar. McGillis then did "Winter People" (1989), an Ozark-based Sturm und Drang, which also flopped. In 1991, she produced the film "The Awakening", which did not receive wide-spread release, and the following year played the woman who marries and tries to tame John Goodman's "The Babe". McGillis joined "Witness" co-star Alexander Godunov in reprising their characters in a brief, amusing cameo for "North" (1994).
McGillis appeared in her first TV-movie in 1984, playing a sister who seeks to punish her sister's tormentor in "Sweet Revenge" (CBS). She followed with "Private Sessions" (NBC, 1985), a busted pilot. In 1993, McGillis played a woman in love with a retarded man in "Bonds of Love" (CBS) and in the 1994 CBS miniseries "In the Best of Families: Marriage, Pride and Madness", she was a woman obsessed with destroying her ex-husband.
McGillis' theater career was interrupted by "Reuben, Reuben", but she returned to the stage in 1988 playing Portia in the Folger Shakespeare Theatre production of "The Merchant of Venice." She has since continued an association with that company, appearing in "Twelfth Night", "Mary Stuart" and "Measure for Measure", among others. In 1994, McGillis made her Broadway debut in the Roundabout Theatre Company's production of "Hedda Gabler".