During his freshman year at Harvard in 2002, Hughes met and was recruited by Mark Zuckerberg, who at the time was still working in the early stages of Facebook. For the next two years, Hughes was unofficially responsible for beta testing and product suggestions. When the group had the idea to open Facebook to other schools, Hughes argued that schools should have their own networks to maintain the intimacy feel. He was also a key driver in developing many of Facebook’s popular features, which led to the opening of Facebook to the outside world. As a result of that, Hughes became the de facto Facebook spokesman.

In 2004, Hughes, Zuckerberg and Moskovitz traveled to Palo Alto during their summer break. After the summer break, while Zuckerberg and Moskovitz decided to remain in Palo Alto, Hughes decided to return to Harvard to continue his studies.

In 2006, he graduated magna cum laude from Harvard University with a Bachelor of Arts in history and literature. He then relocated to Palo Alto to rejoin Zuckerberg and Moskovitz and became involved in Facebook again.

In 2007, Hughes left Facebook to volunteer for Barack Obama’s 2008 presidential campaign.

In March 2009, Hughes was named Entrepreneur in Residence at General Catalyst, a Cambridge, Massachusetts, venture-capital firm.

He was the executive director of Jumo, a non-profit social network organization which he founded in 2010, which “aims to help people find ways to help the world”. In July 2010, UNAIDS (Joint United Nations Programme on HIV/AIDS) appointed him to a 17-member “High Level Commission” of renowned politicians, business leaders, human rights activists, and scientists tasked with spearheading a “social and political action campaign over the coming year aimed at galvanizing support for effective HIV prevention programmes.”

Hughes was portrayed by actor Patrick Mapel in the 2010 film The Social Network.

Hughes is married to Sean Eldridge, political director of Freedom to Marry. Hughes and Eldridge announced their engagement in January 2011 at a reception in support of Freedom to Marry. They married on June 30, 2012. The couple bought a $2 million residence in New York’s 19th congressional district with the reported purpose of permitting Eldridge to run for the congressional seat there. Eldridge lost his 2014 bid for a congressional seat by 28 points.

In March 2012, Hughes purchased a majority stake in The New Republic magazine. He became the publisher and executive chairman, and also served as editor-in-chief of the magazine. In December 2014, shortly after the magazine’s centennial celebration, editor Franklin Foer and literary editor Leon Wieseltier were “driven out” and dozens of other staff and contributing editors resigned after a new chief executive, Guy Vidra, a former Yahoo! employee, described the new direction of the magazine as a “vertically integrated digital media company.” The magazine was forced to cancel its upcoming issue due to the staff departures.

The magazine was not profitable during Hughes’ tenure. On January 11, 2016, Hughes put The New Republic up for sale, saying he had “underestimated the difficulty of transitioning an old and traditional institution into a digital media company in today’s quickly evolving climate.” Hughes’ ownership of The New Republic was described by The New York Times as a “vanity project.” He sold the magazine on February 26, 2016, to Oregon publisher Win McCormack.

In 2019, he wrote an op-ed in The New York Times calling for the break up of Facebook.

In February 2020, it was reported that Hughes was in the process of earning his Master of Arts in Economics from The New School for Social Research in New York City.