After college, Yanagihara moved to New York and worked for several years as a publicist. She wrote and was an editor for Condé Nast Traveler.

Her first novel, The People in the Trees, partly based on the real-life case of the virologist Daniel Carleton Gajdusek, was praised as one of the best novels of 2013.

Yanagihara's A Little Life was published on March 10, 2015, and received widespread critical acclaim. The book was shortlisted for the 2015 Man Booker Prize for fiction, the 2016 Women's Prize for Fiction and won the 2015 Kirkus Prize for fiction. Yanagihara was also selected as a finalist for the 2015 National Book Award in Fiction. A Little Life defied the expectations of its editor, of Yanagihara's agent, and of the author herself, that it would not sell well.

Yanagihara described writing the book at its best as "glorious as surfing; it felt like being carried aloft on something I couldn't conjure but was lucky enough to have caught, if for just a moment. At its worst, I felt I was somehow losing my ownership over the book. It felt, oddly, like being one of those people who adopt a tiger or lion when the cat's a baby and cuddly and manageable, and then watch in dismay and awe when it turns on them as an adult".

In 2015, she left Condé Nast to become a deputy editor at T: The New York Times Style Magazine. She has said that after she published her best selling sophomore novel, people in the publishing industry were baffled by her decision to take a job at T. Describing the publishing world as "a provincial community, more or less as snobby as the fashion industry", she said, "I'd get these underhanded comments like, 'oh, I never knew there were words [in T Magazine] worth reading'". Of working as an editor while writing fiction on the side, she says, "I've never done it any other way". In 2017, she became the editor-in-chief of T.

Yanagihara's third novel, To Paradise, was published on January 11, 2022, and reached number one on The New York Times best seller list.