Cusack has played leading Shakespearean roles in RSC and Royal Court productions of "Macbeth" (as Lady Macbeth), "The Taming of the Shrew" (as Kate) and "The Merchant of Venice" (as Portia). In 1984, she made her Broadway debut opposite Derek Jacobi in the repertory productions of "Much Ado About Nothing" (as Beatrice) and "Cyrano de Bergerac" (as Roxanne), earning a Tony nomination for her work in the former. Six years later, she returned to London's West End for an acclaimed production of "The Three Sisters", co-starring her father and her sisters Sorcha and Niamh.

In the late 1980s, Cusack resumed her big screen career and has co-starred in a handful of mostly European-made features. Her American films have included "Rocket Gibraltar" and "Dublin Murders" (both 1988), while her other credits have included the fantasies "Venus Peter" (1989), "Waterland" (1992) with her husband Jeremy Irons, Les Blair's comedy "Bad Behaviour" (1993), opposite Stephen Rea, and the dramas "The Cement Garden" (1993) and "The Nephew" (lensed 1996). In Italy, she co-starred with Vanessa Redgrave and Johnathon Schaech in Franco Zeffirelli's "Sparrow" (1993) and again teamed with her Irons and Liv Tyler in Bernardo Bertolucci's "Stealing Beauty" (1996).

Cusack made her TV debut in 1970 playing Emily to her father's Barkis in a British production of "David Copperfield". She went to appear in several British-made TV-movies, including the thriller "The Eyes Have It" (1974), two "Quiller" mysteries, "Night of the Father" and "Price of Violence" (both 1975), in which she was cast as a detective's right-hand, "Twelfth Night" (1980), as Olivia, and "Cyrano de Bergerac" (1994), as Roxanne. She and Irons both played supporting roles to Rosemary Harris' George Sand in the multi-part biography "Notorious Woman" (PBS, 1975) and "Tales from Hollywood" (PBS, 1992). More recently, Cusack was seen opposite Alan Bates in the BBC mystery "Oliver's Travels" (1996).