Kepnes was born in Cape Cod, Massachusetts. During her formative years, she attended Barnstable High School. After graduation, she commenced her studies at Brown University. Later, she obtained an undergraduate degree in American Civilization and worked as an entertainment reporter for Entertainment Weekly.
In 2014, Kepnes released her first novel of the thriller series, You. Kepnes explained the darkness of You, which deconstructs the romantic-comedy tropes highlighted in many films and series, by making the interested male a violent stalker, saying it was written in a dark period of her life, the year her father died of cancer, and in which she experienced several other personal challenges.
In February 2015, it was announced that Greg Berlanti and Sera Gamble would develop a television series based on the novel. Two years later, it was announced that the series was purchased by Lifetime and put on fast-track development. You premiered on September 9, 2018. On July 26, 2018, ahead of the series premiere, Lifetime announced that the series had been renewed for a second season. On December 3, 2018, it was confirmed that Lifetime had passed on a second season and that Netflix had picked up the series. The second season was released exclusively on Netflix on December 26, 2019. On January 14, 2020, You was renewed for a third season by Netflix. The third season is scheduled for release sometime in 2021.
In 2016, Kepnes published a sequel to You, Hidden Bodies.
Her third novel, Providence, published in 2018, has been described as romance-suspense-thriller, with supernatural aspects. Alison Flood, in a review published by The Guardian, wrote "Providence is compelling, and Kepnes provides a sometimes piercing insight into the small, strange, sad details that make up a life, though without quite achieving the deep, dark pleasures of You." According to Cheryl Wassenaar, in a review in Cultures magazine, the novel is "a bit like Dexter meets, well, H.P. Lovecraft."
Kepnes is currently working on the third and fourth novels for the You series.