Guerrero was cast in Orange is the New Black in the role of Maritza Ramos, a Bronx-bred character with Colombian roots. For season 2, she was part of the cast that earned recognition for Outstanding Performance by an Ensemble in a Comedy Series at the 21st Screen Actors Guild Awards. The cast earned recognition for Outstanding Performance by an Ensemble in a Comedy Series again at the 22nd Screen Actors Guild Awards and 23rd Screen Actors Guild Awards. She remained part of the show through season 5. She returned for the final season in 2019.

In 2014, Guerrero was cast in a recurring role on The CW series Jane the Virgin. In February 2015, Guerrero was cast as the female lead in CBS‘ television pilot for Super Clyde, but the show was not picked up for series. In 2017, Guerrero was cast in a regular role for season 2 of Superior Donuts. Guerrero has appeared in the films Emoticon 😉, Peter and John, and Happy Yummy Chicken. In 2018, she appeared in the films Beyond Control and The Godmother.

In 2016, Guerrero released In the Country We Love: My Family Divided, a memoir about her parents being detained and deported when she was 14. The book was written with Michelle Burford and published by Henry Holt and Co. A drama based on her memoir was picked up by CBS, to be developed into a drama executive produced by Jennie Snyder Urman, Ben Silverman, and Paul Sciarrotta, with Snyder attached as the showrunner. Guerrero was initially set to play the lead.In 2017, CBS decided to pass on the project, but was picked up by Fox. As of January 2018, no pilot for the series has been ordered.

Following the release of In the Country We Love: My Family Divided, Guerrero also released My Family Divided, a memoir similar to her previous work but for younger children. One of the main reasons she wanted to cater this book to a younger audience is because she felt like kids who were in similar situations as her own had no knowledge on how to deal with it. In an interview with The Washington Post, she says “I never read anything close to my story. I had no reference point. I felt really alone.”

In July 2018, Guerrero joined the cast of the DC Universe series Doom Patrol as Jane.  The series debuted in 2019. She is the first actor to play Crazy Jane onscreen.

Guerrero hosted the first two seasons of the Hello Sunshine podcast, How It Is.

Guerrero provided the voice of Isabela Madrigal in the Disney animated film Encanto, which premiered November 24, 2021.