Born in Boston and raised in Dayton, Ohio, Janney received a scholarship to study at the Royal Academy of Dramatic Art in London following her graduation from Kenyon College.

After years of minor and uncredited film and television appearances, Janney's breakthrough came with the role of C. J. Cregg in the NBC political drama series The West Wing (1999–2006), for which she received four Primetime Emmy Awards.

In 2014, for her guest role of Margaret Scully, a sexually repressed 1950s housewife on Showtime's period drama series Masters of Sex, she won a fifth Emmy.

For her portrayal of Bonnie Plunkett, a cynical recovering addict on the CBS sitcom Mom (2013–2021), Janney won two more Emmys.

Janney has also played character roles in various films, including Primary Colors (1998), American Beauty (1999), The Hours (2002), Juno (2007), Hairspray (2007), The Help (2011), Spy (2015), Bad Education (2019), and Bombshell (2019).

[8] Janney initially aspired to a career in figure skating, but her height of 6 ft (183cm) and a freak accident when she was a teenager put an end to that dream.

[10] She went on to train at the Neighborhood Playhouse School of the Theatre in New York and then received a scholarship to study at the Royal Academy of Dramatic Art in mid-1984.

[14] In the spring of 1994, she appeared in the season-four finale of Law & Order, titled "Old Friends", as a reluctant witness against a member of the Russian mob.

[17] Following minor roles in similar productions like; Prescribed Laughter In The Emergency Café, Five Women Wearing the Same Dress and Blue Window.

[24] This was followed by a series of minor roles in numerous films throughout the 1990s, including; Wolf (1994), Big Night (1996), Private Parts (1997), The Ice Storm (1997), The Object of My Affection (1998), The Impostors (1998), Primary Colors (1998), Drop Dead Gorgeous (1999), 10 Things I Hate About You (1999), and American Beauty (1999).

[25] Janney starred in the Roundabout Theatre Company's 1998 revival of Arthur Miller's A View from the Bridge to positive reviews.

[23][30] After a decade of small and uncredited parts, Janney had her breakthrough when she was cast as White House Press Secretary C. J. Cregg in the NBC political drama The West Wing.

Writing for The Atlantic, John Reid says that "her capability and combination of strength and simple compassion represented the fantasy of the Bartlet White House better than anyone."

[38] In May 2010, she appeared in the antepenultimate episode of the ABC television series Lost as the adoptive mother of the show's two mythological opponents, Jacob and The Man in Black.

[40][41] In 2007, Janney starred in Jason Reitman's comedy-drama Juno, playing Bren MacGuff, the titular character's stepmother.

[50] In 2011, Janney appeared in Tate Taylor's period drama The Help alongside Emma Stone, Viola Davis, Octavia Spencer, Jessica Chastain, Mary Steenburgen and others.

[citation needed] Following few short-lived shows and a brief sabbatical from television, Janney returned to the small screen with the CBS sitcom Mom, which ran from 2013 until 2021.

[55] From 2014 to 2016, Janney guest-starred in Showtime's period drama Masters of Sex, portraying a sexually repressed homemaker in 1950s who struggles to understand the disintegration of her marriage.

[58][59] She voiced Julia in The Simpsons episode "Friends and Family" (2016)[citation needed] and acted as herself in the IFC sketch series Comedy Bang!

[61] Marilyn Stasio of Variety praised Janney's performance writing, "[Her] wicked, smart delivery is perfect for Guare's witty dialogue.

"[62] David Rooney of The Hollywood Reporter concurred writing, "I found I couldn't take my eyes off her...she looks spectacular in costumer Clint Ramos' sleek socialite outfits, and she nails both the initial poise and the despairing needed [for the role]".

[65] Janney's performance received widespread acclaim with Michael O'Sullivan of The Washington Post writing: 'Janney steals every scene she's in, playing LaVona, a harridan whose nodding goes beyond tough love.'

[78] In 2024, Janney began portraying Evelyn Rollins, a socialite in the 1950s in Apple TV+'s period comedy series Palm Royale.

[80] In 2024, Janney began starring in Netflix's political drama The Diplomat as Vice President of the United States Grace Penn.

[88][89] In interviews related to her role on Mom, Janney discussed her brother, Hal, who fought drug addiction for years before his suicide.