Her work often uses self-deprecating and dark topics, including her dysfunctional family, depression, anxiety, suicide and mental illness.

Her film work includes Stuart Little 2 (2002), Charlotte's Web 2: Wilbur's Great Adventure (2003), Barnyard (2006), Heckler (2007), and Hell and Back (2015).

Her live television work began in Louie (2012), Arrested Development (2013–2019), WordGirl (2007–2015), Big Mouth (2017–present), Flatbush Misdemeanors (2021-2022), and Human Resources (2022–2023).

After a year in Scotland, she transferred back to her home state and enrolled at the University of Minnesota, where she earned a Bachelor of Arts degree in English.

She was the voice of Shriek DuBois in Nickelodeon's CatDog, a wide selection of secondary characters in Cartoon Network's Adventure Time, and Mrs. Botsford, Violet, and Leslie on the PBS educational series WordGirl.

[citation needed] Her album Unwanted Thoughts Syndrome, produced by Comedy Central Records, was released in April 2009 and includes a DVD containing The Maria Bamford Show episodes.

During the Christmas 2009–2010 shopping seasons, she was featured in a series of Target commercials, portraying an overachieving shopper determined to be first in line.

[17] During the speech, she gave a check made out to Sallie Mae for $5,000, her net speaking fee, to a graduate in the audience who had student loans.

Zach Freeman of the Chicago Tribune has noted her content and comedic style as "comically erratic" with "seemingly unrelated tangents and constantly varying vocal inflections".

[22] David Sims of The Atlantic noted her roles and voice work as having themes of "serial passivity" stemming from her "polite upbringing and own internal anxieties".

[23] Film producer Judd Apatow has described her comedic style as "complex" and "bizarre", later calling her "the funniest woman in the world".

[4][24] Variety described Bamford's performance in Lady Dynamite, saying that "the actress and comedian, whose presence has rarely been used as well as it is here, manages the neat trick of being both believably guileless and winningly sharp.

Deploying a range of deadpan voices, she mimics the faux enlightened who hover around the afflicted, offering toothless platitudes, bootstrapping pep talks, or concern warped by self-interest.

The humor of any given moment relies not so much on punch lines as it does on the impeccably timed swerves of her tone, the interplay between Bamford's persona and those of all the people who don't get her.