Her role as mob wife Carmela Soprano on the HBO series The Sopranos garnered widespread acclaim, and is often regarded as one of the greatest performances in television history, with Falco winning three Primetime Emmy Awards for Outstanding Lead Actress in a Drama Series.

Cunningham in 30 Rock (2008) and Leslie Abramson in Law & Order True Crime: The Menendez Murders (2018).

Her film work includes lead roles in Laws of Gravity (1992), for which she was nominated for the Independent Spirit Award for Best Female Lead and Judy Berlin (1999), and supporting roles in films including Bullets Over Broadway (1994), Sunshine State (2002), Freedomland (2006), The Comedian (2016), and Avatar: The Way of Water (2022).

She has acted in the Broadway revivals of the plays Frankie and Johnny in the Clair de Lune (2002), and 'night, Mother (2004).

[13][14][15] From the age of four, Falco was raised on Long Island, moving with her family to Hicksville, then North Babylon, and finally West Islip.

[8][16] As a child, she acted in plays at the Arena Players Repertory Theater in East Farmingdale, where her mother also performed.

[8][9][17] Her family eventually moved to Northport, where she attended high school and played Eliza Doolittle in a production of My Fair Lady during her senior year.

[19] Early in her career, Falco made appearances on television shows like Law & Order and Homicide: Life on the Street.

"[20] A struggling actress at the time, Falco said her salary from these television episodes paid for one month's worth of rent.

Her friendship with former SUNY Purchase classmate Eric Mendelsohn, who was the assistant to Allen's costume designer, Jeffrey Kurland, helped her to be cast in the role.

[25] Falco received her breakout role in the HBO drama The Sopranos created by David Chase, which premiered in 1999 and ended in 2007.

[35][36][37] Alessandra Stanley of The New York Times wrote, "It's the compelling, enigmatic heroine who holds the errant pieces together.

"[38] Falco returned to Broadway portraying the part of Bananas in the revival of the John Guare play The House of Blue Leaves (2011) in New York City at the Walter Kerr Theatre with Ben Stiller and Jennifer Jason Leigh.

[40] Theatre critic Ben Brantley of The New York Times wrote in his review for the show, that "Ms. Falco endows the anguished Bananas with such unvarnished emotional transparency — and clinical exactness — that it hurts to look at her.

Along with Falco, the play starred John Ellison, Christopher Evan Welch, Phoebe Strole, and Frances Sternhagen.

series Horace and Pete acting alongside C.K., Steve Buscemi, Alan Alda and Laurie Metcalf.

James Poniewozik of The New York Times noted "Louis C. K. is reportedly submitting “Horace and Pete” for the Emmys as a drama.

for his film I Love You, Daddy (2017) starring C.K., Chloë Grace Moretz, Charlie Day, Rose Byrne, and John Malkovich.

[51] In 2020, she appeared as the lead character in the Paul Attanasio CBS police drama Tommy.

[52] Falco also starred in the FX true crime series Impeachment: American Crime Story (2021) portraying Hillary Rodham Clinton opposite Clive Owen's Bill Clinton and Beanie Feldstein's Monica Lewinsky.

[54] In 2002 Stanley Tucci left his family for Falco, with whom he was appearing on Broadway in Terrence McNally’s Frankie and Johnny in the Clair de Lune, but the affair ended, and he returned to his wife and children.

[57][58] She is a vegan and has worked with PETA on projects, including a public-service message urging parents to keep their children away from the circus.