Bello's early TV appearances include episodes of The Commish (1991), Due South (1994), Nowhere Man (1995), Misery Loves Company (1995), and ER (1997–98).
Her breakthrough came when she was cast as Mrs. Smith in the TV series spy show Mr. & Mrs. Smith, though the show was cancelled after 8 weeks.
She then appeared in the final three episodes of the third season of ER as pediatrician Dr. Anna Del Amico and was a regular cast member during the medical drama's fourth season.

Bello moved on to films, landing a role in Coyote Ugly (2000).
She was nominated for the Golden Globe award twice: for Best Supporting Actress in The Cooler (2003) and for Best Actress in A History of Violence (2005).
She starred in The Jane Austen Book Club (2007) as Jocelyn and as Dr. Alex Sabian in the 2005 film Assault on Precinct 13 a remake of the original 1976 movie originally made by John Carpenter.
In 2008, she starred in The Mummy: Tomb of the Dragon Emperor as Evelyn O'Connell.
In December 2008, Bello began developing a drama for HBO.
Besides starring in the new series, Bello was planned to also serve as an executive producer.
 She starred in the 2009 drama film The Yellow Handkerchief, which was released in theatres on February 26, 2010 by Samuel Goldwyn Films.

In 2010, Bello guest-starred in two episodes of Law & Order: Special Victims Unit.
The following year, she starred in the TV series Prime Suspect, which was cancelled after 13 episodes.
In 2011, she became a founding board member of the CQ Matrix Company, a company created by her then-partner, Clare Munn, to help clients achieve "transformative living and the power of intelligent exchange" by enhancing their communication quotient.
In 2014, she starred alongside Frank Grillo in the James Wan-produced thriller Demonic.
Bello's early TV appearances include episodes of The Commish (1991), Due South (1994), Nowhere Man (1995), Misery Loves Company (1995), and ER (1997–98). Her breakthrough came when she was cast as Mrs. Smith in the TV series spy show Mr. & Mrs. Smith, though the show was cancelled after 8 weeks. She then appeared in the final three episodes of the third season of ER as pediatrician Dr. Anna Del Amico and was a regular cast member during the medical drama's fourth season.
Bello moved on to films, landing a role in Coyote Ugly (2000). She was nominated for the Golden Globe award twice: for Best Supporting Actress in The Cooler (2003) and for Best Actress in A History of Violence (2005). She starred in The Jane Austen Book Club (2007) as Jocelyn and as Dr. Alex Sabian in the 2005 film Assault on Precinct 13 a remake of the original 1976 movie originally made by John Carpenter. In 2008, she starred in The Mummy: Tomb of the Dragon Emperor as Evelyn O'Connell. In December 2008, Bello began developing a drama for HBO. Besides starring in the new series, Bello was planned to also serve as an executive producer.  She starred in the 2009 drama film The Yellow Handkerchief, which was released in theatres on February 26, 2010 by Samuel Goldwyn Films.
In 2010, Bello guest-starred in two episodes of Law & Order: Special Victims Unit. The following year, she starred in the TV series Prime Suspect, which was cancelled after 13 episodes. In 2011, she became a founding board member of the CQ Matrix Company, a company created by her then-partner, Clare Munn, to help clients achieve "transformative living and the power of intelligent exchange" by enhancing their communication quotient. In 2014, she starred alongside Frank Grillo in the James Wan-produced thriller Demonic.
Maria Bello