Flanagan is known for her roles in the films James Joyce's Women (1985), Some Mother's Son (1996), Waking Ned (1998), The Others (2001), Four Brothers (2005), Yes Man (2008), The Guard (2011) and Song of the Sea (2014).

[citation needed] Flanagan made her acting debut as the lead role of Máire in Máiréad Ní Ghráda's Irish-language play An Triail at the Damer Theatre in 1964.

She continued the role in the radio version and rose to national prominence in the Teilifís Éireann television adaptation, for which she won the 1965 Jacob's Award for her "outstanding performance".

She made her Broadway debut in Brian Friel's Lovers (1968), then appeared in The Incomparable Max (1971) and such Joycean theatrical projects as Ulysses in Nighttown (as Molly Bloom) and James Joyce's Women (1977; toured through 1979), a one-woman show written by Flanagan and directed for the stage by Burgess Meredith.

It was subsequently filmed in 1983, with Flanagan both producing and playing all six main female roles (Joyce's wife, Nora Barnacle, as well as fictional characters Molly Bloom, Gerty McDowell, etc.).

[8][9] A familiar presence in American television, Flanagan has appeared in several made-for-TV movies including The Legend of Lizzie Borden (1975) starring Elizabeth Montgomery, Mary White (1977), The Ewok Adventure (1984) and A Winner Never Quits (1986).

Subsequently, she spoke at a memorial hosted by Sinn Féin at the Citywest Hotel in Dublin for Irish republicans and their kin who were killed during the latest episode of the Troubles in Northern Ireland.