For her performance in Delhi Belly, Jagannathan won the Stardust award for Best Supporting Actress and the L'Oreal Femina Award for Breakthrough Performance in 2012.

Jagannathan is an established theater Actress and is a board and company member of The Barrow Group in New York City. In 2012, Deadline.com reported that Jagannathan had joined the cast of HBO's new show The Night Of as a series regular. The ensemble cast was led by James Gandolfini and was written and directed by Steven Zaillian and Richard Price. The project was shot at the end of 2012 but was shelved by HBO. It got revived in May 2013 and was slated to start shooting again with Gandolfini in 2014. After Gandolfini's death, Oscar winner Robert De Niro initially stepped in to take over the role originally played by the beloved Sopranos star in the pilot. Due to schedule conflicts, John Turturro replaced De Niro. Filming resumed August 2014 and ended in March 2015 in New York City. The Night Of released on HBO on July 10th, 2016 to critical acclaim. On Metacritic, it currently has a score of 90%, indicating "universal acclaim" based on 40 reviews. It currently has a score of 95% on Rotten Tomatoes with an average rating of 8.5/10 based on 56 reviews; its consensus reads, "The Night Of is a richly crafted, exquisitely performed mystery that will keep viewers enthralled and leave them devastated."

On September 2016, it was announced that Jagannathan was joining the cast of Gypsy as a series regular. The Netflix produced series was led by Naomi Watts and released on June 30th, 2017. In August 2017, Netflix announced it would not renew Gypsy for another season.

Jagannathan won critical acclaim for her role as a spunky, irreverent Journalist in the film Delhi Belly. The Village Voice said "For all this censor-board razzing, the most enjoyably subversive element is Poorna Jagannathan as the self-sufficient bachelorette who waylays Tashi on his way to the altar. Rangy, corkscrew-haired, with a wary demeanor that can’t long be upset by anything, she’s a happy departure from the usual run of Xeroxed, pedestaled beauties." Mumbai Mirror said, "Poorna Jagannathan, an offbeat choice, is remarkably subtle and does a brilliant job." The Daily News and Analysis said that Jagannathan shines in the film, and that "her bohemian sex appeal" is "a refreshing change from the prim and proper 'heroine' we are used to watching." The Editor of Outlook Lounge said that Jagannathan's performance was a "masterclass in effortless acting".