Wilde made her directorial debut with the teen comedy film Booksmart (2019), which received critical acclaim and won the Independent Spirit Award for Best First Feature.

[10] She derived her professional surname from Irish author Oscar Wilde,[10] and began using it in high school to honor the writers in her family, many of whom used pen names.

She gained attention for her recurring role as bisexual bar owner Alex Kelly, who dates both characters played by Adam Brody and Mischa Barton on the teen drama TV series The O.C.

[13] She appeared in films The Girl Next Door (2004), Conversations with Other Women (2005), Bickford Shmeckler's Cool Ideas (2006), Turistas (2006) and Alpha Dog (2006).

In August 2011, it was announced Wilde would be leaving House to further pursue her film career; she left a few months later, in the episode "Charity Case".

In 2012, Wilde was featured as one of six celebrity advocates in the PBS docu-series Half the Sky: Turning Oppression into Opportunity for Women Worldwide, which was inspired by Nicholas Kristof and Sheryl WuDunn's book of the same name.

[21] Wilde starred as Elizabeth Roberts, a trophy-wife customer who enters a strait-laced pharmacist's life and takes him on a joyride involving sex, drugs and possibly murder in Better Living Through Chemistry (2014).

[23] She starred in the thriller The Lazarus Effect (2015) as Zoe, a medical researcher who is accidentally killed, then revived with a miraculous serum with unfortunate side-effects.

In 2016, Wilde directed a music video for Edward Sharpe and the Magnetic Zeros, teaming up with director of photography Reed Morano.

She then worked with American rock band Red Hot Chili Peppers, directing the music video for their song "Dark Necessities".

Also in 2016, Wilde also directed an acclaimed live table reading of Hannah and Her Sisters at The New York Times's Center Theatre.

[28] Wilde stated that Hannah and Her Sisters is "just a perfect script, and I knew an audience would enjoy having the chance to focus on the genius of the writing, which is what the Live Reads allow for".

[31] Her documentary short Fear Us Women (2017) follows Canadian civilian Hanna Bohman, who has spent the last three years in Syria as a volunteer soldier battling ISIS.

[41] The Washington Post stated, "[as the film progresses,] Wilde's filmmaking skills become more and more evident, bursting forth in a third act that builds into something beautiful and even transcendent."

[43] The film was criticised for depicting Scruggs as offering to trade sex with an FBI agent in return for confidential information.

[44] Wilde defended her role and stated that there was a sexist double standard, in that Jon Hamm's FBI agent character was not held to the same scrutiny.

[47] In 2022, she directed her second feature, also playing a supporting role in, Don't Worry Darling, an erotic psychological thriller about a 1950s housewife,[48] starring Florence Pugh, Harry Styles, Gemma Chan and Chris Pine, for New Line Cinema from a screenplay by Katie Silberman.

[58] In 2008, Wilde campaigned with actors Justin Long and then-current House castmate Kal Penn in support for Democratic presidential nominee Barack Obama.

[62] In 2013, Wilde appeared in a video clip for Gucci's "Chime for Change" campaign that aimed to raise awareness of and funds for women's issues in education, health and justice.

[63] As of 2013, she is on the board of directors of Artists for Peace and Justice, which provides education and health services in Haiti;[64] and of the American Civil Liberties Union of Southern California.

[65] On June 30, 2015, Wilde introduced Democratic presidential candidate Hillary Clinton at a campaign event in New York City.

[68] In 2022, Wilde recorded Ada Limón's poem Lies about Sea Creatures as part of For the Birds: The Birdsong Project,[69] whose proceeds benefitted The National Audubon Society.