She starred in Pretzels, an off-Broadway play written by Curtin, John Forster, Judith Kahan, and Fred Grandy, in 1974.

One of the original Not Ready For Prime Time Players of NBC's Saturday Night Live (1975), Curtin remained on the show through the 1979–1980 season.

Guest host Eric Idle said that Curtin was "very much a 'Let's come in, let's know our lines, let's do it properly, and go' ... She was very sensible, very focused", and disliked the drug culture in which many of the cast participated.

[11] On the show, and mirroring her own low-key real life, she frequently played straight-woman characters, often as a foil to John Belushi and Gilda Radner.

On occasional "Weekend Update" segments, her newscaster character served as a foil to Belushi, who often gave a rambling and out-of-control "commentary" on events of the day.

In a parody of the "Point-Counterpoint" segment of the news program 60 Minutes, Curtin delivered a controlled liberal viewpoint (à la Shana Alexander) vs. Aykroyd, who (in the manner of James J. Kilpatrick) epitomized the right-wing view, albeit with an over-the-top "attack" journalist slant.

Then Aykroyd presented the "Counterpoint" portion, sometimes beginning with the statement, "Jane, you ignorant slut," to which she replied, "Dan, you pompous ass."

The series was created by Bill Persky, a writer, director, and producer of Kate & Allie, but it was not successful and was cancelled after 13 episodes.

Later, she was part of the cast of 3rd Rock from the Sun (1996–2001) playing a human, Dr. Mary Albright, opposite the alien family composed of John Lithgow, Kristen Johnston, French Stewart, and Joseph Gordon-Levitt.

[15] In 2012, she joined Unforgettable as Dr. Joanne Webster, a gifted but crusty medical examiner; in 2014, she occasionally reprised her role as the first Guardian on The Librarians.

In 1980, Curtin starred with Susan Saint James and Jessica Lange in the moderate hit How to Beat the High Cost of Living.

In 1993, Curtin and Dan Aykroyd were reunited in Coneheads, a full-length motion picture based on their popular SNL characters.

She later went on to be a replacement actress in two other plays, Love Letters and Noises Off, and was in the 2002 revival of Our Town, which received huge press attention as Paul Newman returned to the Broadway stage after several decades away.

[17] Curtin has guest hosted several episodes of Selected Shorts produced by Symphony Space and distributed by Public Radio International.