After making her acting debut in the comedy Rob (2012), Ortega made an appearance in the CSI: NY episode “Unspoken” as a victim of an unintentional gunshot. She debuted in a small part in the superhero movie Iron Man 3 in 2013 as the daughter of the vice president. Ortega had a supporting cast appearance in the horror movie Insidious: Chapter 2 in the same year. At the box office, both movies did well, with the former being one of the all-time biggest grossing movies.

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In the comedic television series Jane the Virgin on The CW, which ran from 2014 to 2019, Ortega played a recurring role as a younger Jane Villanueva, played by Gina Rodriguez in her adult role. Ortega said that she didn’t have “anything overwhelmingly special” about her audition and blamed her casting on Rodriguez’s likeness. Congratulating Ortega on her performance, Declan Gallagher of Entertainment Weekly said that “she eschews the trappings of a typical child actor”. Additionally, Ortega appeared in the Netflix series Richie Rich (2015) and the direct-to-video comedy film The Little Rascals Save the Day (2014). As Anna Chapa, Ortega had an appearance in the 2015 movie After Words. She was called “adorable” by The Los Angeles Times and “horribly cloying” by The Arizona Republic.

As the middle kid out of seven siblings and an ambitious inventor named Harley Diaz, Ortega starred in the Disney Channel sitcom Stuck in the Middle from 2016 to 2018. “One of the best days of my life” was her statement upon receiving the part. Ortega thought that being a celebrity on the program was similar to reality television, and she took inspiration from her own family and her interactions with her brothers. Ortega “commands this role, pleading her case as a long-suffering middle kid while finding the humor in the many calamities that befall her efforts to shine,” according to Common Sense Media, which applauded her performance. Three Imagen Award nominations for Best Young Actor—Television went to Ortega, who won the title in 2018. In Elena and the Secret of Avalor (2016) and Elena of Avalor (2016–2020), she also provided the voice of Princess Isabel.

In 2018, Ortega played the title character of Dawn, the daughter of a circus owner, in the movie Saving Flora. Ortega wanted to perform in more adult parts once Stuck in the Middle ended, but he discovered that many thought Disney roles were “all you can do, or all you were meant for.” She said she “was too old for the younger roles and too young for the older roles” and she thought about giving up acting on many occasions. In the second season of the Netflix thriller series You, which debuted on December 26, 2019, Ortega was cast as Ellie Alves in 2018. Similar to the previous season of the show, Robyn Bahr of The Hollywood Reporter praised Ortega as “a standout performer” in the second season’s favorable reviews. In retrospect, Ortega praised the creative freedom she was granted and stated the performance is “easily one of my favorite sets that I’ve ever, ever been on.” Due to schedule issues, she was unable to make her third and fourth season comeback.

In the Netflix horror movie The Babysitter: Killer Queen, which debuted in September 2020 to unfavorable reviews from critics, Ortega portrayed Phoebe. In the 2020–2022 Netflix animated series Jurassic World Camp Cretaceous, Ortega again provided Brooklynn’s voice. She published her first novel, It’s All Love, in 2021. Subsequently, Ortega portrayed a resolute adolescent who longs for greater autonomy from her parents in the Netflix comedy film Yes Day (2021). She said that rather than “shoving it down your throat,” the film’s portrayal of people of color was presented in “a casual setting where it’s acknowledged,” and it “could be a really good thing for young people of color to see.” Mixed reviews greeted the March 2021 publication of Yes Day. Ortega was praised as “very capable” by IndieWire and as “an impressively poised young actor” by the Associated Press.

In the drama film The Fallout, Ortega played a high school girl attempting to deal with her emotional scars from a school shooting. She studied pictures, watched interviews, and videos of school shootings to be ready for the part; thinking back on the incidents “kind of came naturally” thereafter. She also made an effort to take part in the March for Our Lives campaign, which organized protests in favor of gun control laws in the United States. Depicting the relatability of her character came naturally to Ortega, who considers herself as “such an insecure individual”. On March 17, 2021, The Fallout had its South by Southwest debut. On January 27, 2022, HBO Max released the film. Critics gave the movie a favorable review, and Ortega’s performance was praised. Her portrayal was hailed as “grounded and deeply moving” by Chicago Sun-Times reporter Richard Roeper, while The Hollywood Reporter noted that her “beautifully nuanced turn understands the nothing-to-look-at-here façade and the chinks in the armor”.