Wu's breakthrough role came with the ABC sitcom Fresh Off the Boat (2015–2020), which earned her four nominations at the Critics' Choice Television Awards.

On television, she appeared in episodes of Law & Order: Special Victims Unit, Torchwood, and Covert Affairs, and had a recurring role as Laudine Lee on the ABC soap opera One Life to Live in 2007.

[19][20] In 2014, Wu participated in Sundance Screenwriters' Lab with two emerging Asian-American directors, Yung Chang and Christopher Yogi, in what she felt was a unique opportunity to support fellow Asian storytellers.

[21][22] The series is loosely based on the life of chef and food personality Eddie Huang and his book Fresh Off the Boat: A Memoir.

[4] In February 2017,[31] Wu was cast as the female lead in Jon M. Chu's adaptation of Crazy Rich Asians, based on the bestselling novel of the same name by Kevin Kwan.

[37] The following year, the actress starred alongside Jennifer Lopez in the crime comedy film Hustlers, which follows a group of former strippers in Manhattan who rob wealthy men.

[40] The film opened on September 13, 2019, and became a box office success, grossing over $157 million worldwide and receiving positive reviews from critics.

[43] In June 2019, it was announced that Wu would play the lead role in a film titled Goodbye Vitamin, based on the debut novel of Rachel Khong.

alongside Neil Patrick Harris, Jane Krakowski, and Debra Messing in an off Broadway play written and directed by Robert O'Hara.

Wu has shared her stories regarding times that she had been denied roles due to her racial background, and stated her hopes that her success would pave more paths for diverse representation in the U.S. film industry.

[53] The #StarringConstanceWu hashtag meme, adopted by Asian-American activists, inserts Wu's image into film promotional materials in order to highlight the lack of actors of Asian descent in starring roles.

[54][55] In 2017, Wu worked with Miry's List, an organization that provides essential kits to newly arrived immigrants and refugee families in Southern California, stating in an interview with Teen Vogue that she wants to be active in her care of "people with the courage to make an immigrant journey in search of peace, safety and well-being for their families.

"[56] In 2023, Wu was one of the actors to sign an open letter praising President Joe Biden advocating for the release of the October 7th hostages.

She signed alongside Gal Gadot, Bradley Cooper, Madonna, Bob Odenkirk, Taika Waititi, Tyler Perry, and Zoe Saldana.

[73] Several days later, Wu clarified that she had been angry at the show's renewal because it had forced her to drop out of another project which she was "really passionate about", one that would have been an artistic challenge compared to her role in Fresh Off the Boat.

Wu abstained from social media for the subsequent three years and decreased her acting workload to "focus on [her] mental health", which included entering psychotherapy.

[75] In September 2022, Wu stated in interviews that she was the target of sexual harassment by an unspecified producer of Fresh Off the Boat which had contributed to her initial reaction to the news of the show's renewal.