In May 2016, Mendes graduated from New York University Tisch School of the Arts. While there, she would also became friends with singer Maggie Rogers. In 2018, Mendes appeared in the music video for Rogers' song "Give a Little". She would later state that she was "roofied and sexually assaulted" during her time at NYU, which inspired her to get a tattoo above her rib saying "to build a home".
In 2016, Mendes was cast as "silver-tongued high school sophomore" Veronica Lodge in The CW's teen drama series Riverdale, a subversive take on the Archie Comics. Mendes was represented by the Carson Kolker Organization, later changing to CAA.