Greer expanded into multiple genres with roles in films, such as The Wedding Planner (2001), Adaptation (2002), The Village (2004), The Descendants (2011), Jeff, Who Lives at Home (2011), Carrie (2013), Men, Women & Children (2014), Grandma (2015), Lemon (2017), Where'd You Go, Bernadette (2019), Uncle Frank (2020), and Hollywood Stargirl (2022).

On television, Greer is best known for her starring voice role as Cheryl Tunt in the FXX animated comedy series Archer (2009–2023) and as Lina Bowman in the FX sitcom Married (2014–2015).

She also appeared in the comedy series The Big Bang Theory (2007–2019), Arrested Development (2003–2006, 2013–2019), Two and a Half Men (2003–2015), It's Always Sunny in Philadelphia (2007–2011), Kidding (2018–2020), Let's Go Luna!

She was cast in her first major role as Fern Mayo, a nerdy teenager who uncovers her classmates' murder of their friend, in Darren Stein's black comedy Jawbreaker (1999).

[20][21] Greer then played another supporting role in Jenna Fischer's directorial debut, the comedy LolliLove, which premiered at the St. Louis International Film Festival to positive reviews from critics, though it was ultimately released straight-to-DVD.

[26] Ty Burr of the Boston Globe called the film "an actor's playpen", and remarked that "Greer has been stuck so long in goofball supporting roles that she tears into this part – a smart, loving mother frightened of her own son – as if it were prime rib.

"[27] Following an appearance in the drama In Memory of My Father, Greer featured in Cameron Crowe's tragic-romantic comedy Elizabethtown, starring Orlando Bloom, Kirsten Dunst, Alec Baldwin and Susan Sarandon.

[28] Following an appearance in Paul Weitz's comedy American Dreamz, Greer starred in the comedy-drama The TV Set (both 2006), as a personal manager to the scriptwriter (David Duchovny) of a television series.

[30][31] Dana Stevens of Slate noted that "[...] Judy Greer, an Anne Heche lookalike with Lisa Kudrow's comic timing, nearly steals the movie as Mike's desperately chirpy manager.

[34][35] During this period, Greer became a frequent guest star for producer Chuck Lorre, having appeared in his sitcoms Two and a Half Men (2007–2015), The Big Bang Theory (2010), and Mom (2015).

[36] In 2008, Greer starred opposite Zach Galifianakis in the independent satire Visioneers, and played the best friend of a bridesmaid in the romantic comedy 27 Dresses.

[60][61] That same year, Greer also starred in the comedy-drama Jeff, Who Lives at Home, directed by brothers Jay and Mark Duplass, in which she and Ed Helms played a couple whose marriage is failing.

[67][68] Greer also hosted an online series of exercise videos titled Reluctantly Healthy, which was later adapted by Litton Entertainment as part of their Saturday-morning One Magnificent Morning block for The CW.

[70][71] The play received negative reviews, with Ben Brantley of The New York Times criticizing Greer for not "transcend[ing] her character's function as a visitor-from-another-planet plot device.

[74] Nevertheless, Michael Phillips of the Chicago Tribune, who gave the film a positive review, remarked, "The acting's strong; in addition to Moretz and Moore, Judy Greer is a welcome presence in the [...] role of the sympathetic gym instructor.

[82][83] Greer then played a supporting role in Jason Reitman's drama Men, Women & Children, which premiered at the Toronto International Film Festival.

[84][85] The film was widely panned by critics, with Jason Bailey of FlavorWire criticizing the plot surrounding Greer's character, a single mother promoting her daughter on a modeling website: "I cannot begin to tell you how effectively this wholly unbelievable thread manages to single-handedly unravel the narrative, but I can assure you that when even Judy Greer can't sell a plot point, it should not be employed.

"[86][87] That same year, Greer made her directorial debut with the AOL short film Quiet Time, which focuses on how transcendental meditation can be used for stress relief.

[88] Greer also released her first autobiographical collection of essays, titled I Don't Know What You Know Me From: Confessions of a Co-Star, which details her life experiences and career in the film industry.

[89] The book received positive reviews; Kirkus Reviews noted that "This is not a Hollywood roman à clef; Greer doesn't dish and is amazed by and grateful for her good fortune [...] Greer is an engaging and witty storyteller, at turns wistful (of her beloved hometown, she writes, "Detroit is America's sad family member who can't catch a break") and unsparingly honest ("I used to be more ugly").

"[119] The film stars Allison Janney, Katie Holmes, Bradley Whitford, Jennifer Garner (Greer's co-star from 13 Going on 30) and rapper Common, and received largely negative reviews from critics.

[120] In 2018, Greer first played a supporting role in Clint Eastwood's biographical film The 15:17 to Paris, as the mother of U.S. Air Force Staff Sergeant Spencer Stone.

As part of an overall negative response, Tim Grierson of ScreenDaily lamented that Greer and co-star Jenna Fischer were "trapped playing supportive-parent clichés.

[125][126] Greer starred with Jamie Lee Curtis in Halloween (2018), a direct sequel to John Carpenter's original 1978 horror film, in which she played the daughter of Laurie Strode.

[147][148] Greer then appeared in the musical romantic comedy Valley Girl, a remake of the 1983 film of the same name, in which she played Julie Richman's mother, in a role originated by Colleen Camp.

"[155][156] Greer next provided the voice of Martha Washington in Netflix's adult animated film America: The Motion Picture, which received negative reviews from critics.

[159][160] Brian Truitt of USA Today considered the film to be a step back in the franchise, but was nonetheless impressed by Greer's performance, "with Karen proving herself worthy of the Strode name.

[166] Courtney Howard of Variety commended Greer for bringing "depth and dimension to Ana, providing a nuanced sense of parental guilt in balancing dreams with pragmatic reality.

Club described Greer's performance as "uncharacteristically wily [...] refusing to admit that she may have fingered the wrong guy and crafting any number of implausible theories to make that accusation stick.

[180][181] Tom Long of The Detroit News remarked that "All the actors are in fine form, but Greer still manages to stand out, building a Bree that's self-involved and silly but still a bit sexy and warm.