After graduating from the University of Waterloo in 1999 with a degree in electrical engineering, Palihapitiya worked for a year as a derivatives trader at the investment bank BMO Nesbitt Burns. He moved to California to be with his then-girlfriend, Brigette Lau, and they later married. In 2018 Palihapitiya filed for divorce. Palihapitiya currently lives in California with his girlfriend Nathalie Dompe, an italian pharmaceutical heiress and model.

Palihapitiya joined AOL, becoming the company’s youngest vice president ever, heading its instant messaging division in 2004. In 2005, he left AOL and joined Mayfield Fund; a few months later he left that job and joined Facebook, which was then a little more than a year old. Palihapitiya’s work at Facebook involved trying to increase its userbase.

In 2011, he left Facebook and started his own fund, The Social+Capital Partnership, with his wife. The firm changed its name to Social Capital in 2015. It has stood out strategically, with a focus on technology in healthcare, financial services, and education, as well as on software as a service. Social Capital started investing in health and education when those fields were largely neglected by other venture capitalists.

Palihapitiya has three World Series of Poker (WSOP) and two World Poker Tour (WPT) cashes for a total of $175,801. In 2011, he finished 101st out of 6,865 entries in the World Series of Poker’s Main Event.

In March 2013, Palihapitiya confirmed that his venture fund had raised more than $275 million in its second round of fundraising. As of 2015, the fund had more than $1.1 billion in total assets.

Palihapitiya was listed as one of the “Founders” of the lobbying group FWD.us. The group launched on April 11, 2013, and its goals include immigration reform, improving education, and enabling technological innovation, all in a United States context. An article in The New Republic stated that Palihapitiya received a weekly report about FWD.us and also quoted him as saying, in response to controversy around the FWD.us political lobbying strategy: “The folks that are actually people that run that day to day are sophisticated and understand the nuances of how to affect it… It’s a really gnarly, gnarly thing having to deal with Washington. And to be honest with you, my perspective was, it’s a really good investment because it’s a good way to pay it forward, and I’m really glad there are other people other than me who are dealing with it who have the patience and resolve to figure it out.”

In October 2015, Palihapitiya and Social Capital worked with the technology industry publication The Information to publish a report on diversity in venture capital. The study found that 92% of senior investment teams at top-tier venture firms are male and 78% are white. Based on the report, Palihapitiya wrote an op-ed calling for a “wake-up call” among venture capital firms that would “recapture our potential and open doors” in order to “surround ourselves with a more diverse set of experiences and…prioritize a diverse set of things.”

Through the fund, Palihapitiya has invested in a number of companies, including Glooko, Inc, Yammer, SecondMarket, Slack, Box, and Premise. In 2017 he became a member of the board of directors of Slack.

In November 2017, Palihapitiya said that, for ethical reasons, he regretted helping Facebook to become the largest social media platform. He said,

The year 2018 saw a decline in the Social Capital fund’s operations and a massive exodus of top management and co-founders.

In 2019 Palihapitiya stepped down as a member of the board of directors of Slack.

In 2020, Palihapitiya helped take Virgin Galactic public.