Cox, 36, worked closely with Zuckerberg through the company's ups and downs, having joined up about 20 months after Facebook was hatched in 2004 in Zuckerberg's Harvard dorm room.
In his post, Zuckerberg announced further reorganization of the company's top ranks and the departure of Chris Daniels, another executive who ran Internet.org, the company's philanthropic project to promote global internet access, and was recently promoted to lead WhatsApp.
Zuckerberg said Cox first mentioned he might leave a few years ago, but made a decision to stay on after 2016 as evidence emerged that Russians had manipulated Facebook's services to provoke discord in the US and influence the election won by President Donald Trump.
In his blog post, Zuckerberg said that Cox had told him that he planned to move on several years ago, but that Cox chose to hold off on leaving until the company made more progress combating misinformation and Russian meddling - controversies that erupted in the wake of the 2016 election. In May, Cox was put in charge of Facebook's "family of apps", including Instagram, Messenger, WhatsApp and Facebook itself - which together have over 2.7 billion users worldwide.
Zuckerberg said he has no plans to replace Cox, though Daniels will be replaced by Will Cathcart, another longtime Facebook veteran. He pocketed $310 million in gains from exercising Facebook stock options from 2014 through 2017 alone, according to the company's filings with securities regulators. Daniels is leaving less than a year after WhatsApp founder Jan Koum resigned in an apparent dispute with Zuckerberg over the future direction of the widely used messaging service.
The departures of Cox and Daniels come a day after a technical issue that limited use of Facebook and Instagram for most of Wednesday. In a memo to employees, Zuckerberg suggested the events were linked.
Daniels took the helm of WhatsApp after founders Jan Koum and Brian Acton left the messaging app past year, reportedly over disagreements about the increased integration of WhatsApp's operations with Facebook's.