She began her career playing roles in the Mexican telenovelas Siempre tuya Acapulco (2013) and Tanto amor (2015), and then the series Club de Cuervos (2017).

[5] In 2013, she was part of the duet Melissa y Sebastian, with whom she recorded her first album and had her first top ten radio hit with their debut single "Mamma Maria", a cover of Ricchi e Poveri's song from the 1980s.

In 2015, she recorded the theme song "Volver a caer" alongside the Mexican singer Kalimba, for her telenovela Tanto amor.

[11] The film earned widespread critical acclaim, with Monica Castillo of The Wrap praising Barrera's performance: "Vanessa's upbeat salsa anthem, 'It Won't Be Long Now', is perhaps one of the more underrated sequences: It's an impressive showcase for Barrera's talents, giving her a wide range of emotions to move through in one number and one of the few moments in the musical to belt out.

[18][19] In early 2023, Barrera reprised her role as Sam Carpenter in Scream 6, which scored the highest opening weekend of the franchise.

The firing was a result of social media posts she had made which described Israel's actions in the Israel–Hamas war as "genocide and ethnic cleansing".

Following her firing Barrera released a statement which denounced antisemitism and Islamophobia and said criticism of a government should not be conflated with attacks on the people of a country.

[26] Barrera met musical artist Francisco Xavier Zazueta on the set of La Academia in 2011, and performed a rendition of Enrique Iglesias' "Cuando Me Enamoro" for its fourth episode.