She spent a majority of her career in theatre, making her Broadway debut in the 1982 Beth Henley play Crimes of the Heart.

Her other notable films include 84 Charing Cross Road (1987), Mighty Aphrodite (1995), Sabrina (1995), In & Out (1997), You Can Count on Me (2000), Margaret (2011), and Christine (2016).

[19] She appeared in the Paul Rudnick play The Naked Truth Off-Broadway at the WPA Theatre in 1994,[20] for which she received a Drama Desk Award nomination.

[21] From November 1999 through April 2000, she appeared as Clare in Fuddy Meers at New York City Center, Stage II, for which she was nominated for the Outer Critics Circle Award as Outstanding Actress in a Play.

[23] In November through December 2009, she appeared Off-Broadway at the Acorn Theatre in her husband Kenneth Lonergan's play The Starry Messenger.

The New York Times' theatre critic Charles Isherwood wrote: "In one of the finest performances of her distinguished career on the New York stage, Ms. Smith-Cameron imbues her Juno with a steely pragmatism, but more important an emotional pliancy that makes her more prepared than the rest of her clan to beat back the onslaughts of ill fortune that beset them.

[28] In 2024 she made her West End debut in the revival of Juno and the Paycock opposite Mark Rylance at the Gielgud Theatre.