She made her professional debut in 2004 in the recurring role of Adriana Cramer in the television soap opera One Life to Live.

[8] When she was accepted to New York University (NYU), which she called her "dream school",[9] she thought she would be unable to attend due to the cost.

[11] Hours after her final exam at NYU, she was offered the role of Adriana Cramer on the soap opera One Life to Live (OLTL), which she described as "the biggest redeeming moment".

[1] She was set to leave the show shortly after her contract with OLTL expired in January 2008,[13] but stayed until June 11;[14] her final scenes were filmed in May.

For the role, she learned the character's Spanish Harlem accent—a task she found difficult—and extensively trained in stretching and yoga to perform the modern and contemporary dance.

[a] Fumero's first starring role and breakthrough came in 2013,[20][8] when she was cast in Fox's untitled comedy pilot as the female lead opposite Andy Samberg.

[25] Fumero is one of the show's two regular Latina cast members, the other being Stephanie Beatriz, who portrays Rosa Diaz.

[11] Due to her lack of experience in comedy, Fumero was usually nervous, a trait the writers incorporated into Amy's personality.

[c] Reception of Fumero's performance was positive; Collider lauded her comedic timing, drive, and vulnerability,[36] while Entertainment Weekly found her acting convincing in a scene in which Amy tells Jake (Samberg) "[n]othing's going to happen" between them romantically.

[38] In 2015, the show's cast were nominated for a Screen Actors Guild Award for Outstanding Performance by an Ensemble in a Comedy Series.

[44] Fumero said she found comic acting much easier, having become more familiar with Amy's character, and added she had "fallen into a real groove and rhythm" with her approach to scenes.

After the network ordered five additional episodes, and Joe Lo Truglio and Beatriz told her they were applying, Fumero did so as well.

[64] In 2020, her vocal performance in Disney Junior's Elena of Avalor as Antonia—the titular character's seamster and later the first female member of the royal guard[65]—Fumero earned her fourth Imagen Award nomination for Best Supporting Actress.

[68] In the animated series M.O.D.O.K., Fumero voiced Melissa Tarleton, the titular character's 17-year-old daughter who wants to gain his approval as a supervillain.

[72] Commenting on Fumero's voice acting, Comic Book Resources said she "[brings Melissa] to life with just the right amount of teenaged moodiness".

[73] Brooklyn Nine-Nine's eighth and final season began its broadcast on August 12, 2021, with the episodes "The Good Ones" and "The Lake House".

[79] Fumero compared the experience of leaving Brooklyn to high-school graduation: [Y]ou're so proud that you did the thing and you reached this moment, but you're also so sad because deep down, you know all your friends are going to different colleges and you're never going to see them again.

[82] Fumero thought the script was "amazing" and accepted the role, partially because she wanted to work with Ramos and lead actor Randall Park.

[81] Fumero "immediately connected" to her character Eliza, a devoted mother who is experiencing difficulties with her marriage to her teenage boyfriend.

It follows former couple Nina (Fumero) and Allen (Luka Jones), who to avoid drama after their breakup divided everything in their lives—except their favorite local bar, an omission that causes a battle between them.

[89] Elizabeth Weitzman of TheWrap said Fumero and co-star Rachel Bloom "don't have the BFF chemistry both actresses work hard to generate, but that's because the characters are all sketched in two dimensions".

[91] Fumero also directed two episodes of the 2023 sitcom Primo, which was created by Shea Serrano and co-executive produced by Brooklyn Nine-Nine's co-creator Michael Schur.