After college, Wortham moved to San Francisco, where she interned for San Francisco Magazine and Girlfriend Magazine and wrote for SFist, eventually becoming a technology and culture reporter for Wired. She joined The New York Times in 2008, working as a technology and business reporter, then moved to the Times Magazine in 2014; Politico said the hire "gives the magazine additional editorial firepower and cachet," citing Wortham's "huge following" including more than 530,000 Twitter followers as of December 2014. Wortham's work has also appeared in Matter, The Awl, Bust, The Hairpin, Vogue, The Morning News, and The Fader among other publications. Pi.co calls her "one of those rare writers who is able to explain the shapeshifting culture of the younger and newer internet." In 2012, Wortham was included in the Root 100 list. The Fader named Wortham's piece on The Shade Room "Instagram's TMZ" to its list of "The Best Culture Writing of 2015." In addition to praise for her technology reporting, Wortham has been recognized for her commentary on a range of cultural topics. At The Village Voice, Mallika Rao described Wortham as "skirt the edges of tech, culture, and identity in her writing — carving out her own corner of the internet wherein she is a rightful star. " Other topics in Wortham's writing have included queer identity and race and gender on television. At Rookie, Diamond Sharp praised Wortham's "incisive writing, and the generous way she moves within the world. She is, with no hyperbole, one of the most important minds working in media." Wortham is co-writing a book with Kimberly Drew entitled Black Futures, due out in December 2020 from Chris Jackson's One World imprint at Random House.
In 2011, Wortham created Girl Crush Zine with Thessaly La Force, a project After Ellen said aimed "to show women embracing their love for other women." Other contributors included fiction writers Jennifer Egan and Emma Straub—with Straub writing about her girl crush on Egan. In November 2014, Wortham debuted an ongoing project called Everybody Sexts which "collect anecdotes of people’s sexting decisions, accompanied by nudes from said sexting incidents that are then recreated by an array of artists," including Melody Newcomb. Vice Media's technology vertical Motherboard said Wortham's treatment of sexting was "one of the first to transcend hand-wringing or how-to guides, and present the sexual behavior as something worthy of inspiring art."