"While it is sad to lose such great people, this also creates opportunities for more great leaders who are energized about the path ahead to take on new and bigger roles", Zuckerberg said. "As part of this, I'm sad to share the news that Chris Cox has chose to leave the company", he wrote.
Mr Cox was one of Facebook's first software developers and one of the chief architects of the news feed, the cascade of Facebook posts that is the company's most lucrative source of advertising.
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.
Like many other longtime Facebook executives, Cox is unlikely to ever have to work again if he doesn't want to.
While Cox gave no specific reason for his move, he noted that Facebook chief Mark Zuckerberg has unveiled a new direction away from being the "digital town square" to focus on smaller-scale, private interactions.
Zuckerberg, in a separate post, said Cox had discussed the possibility of moving on "for a few years", but had remained for a transition period.
Zuckerberg told Wired magazine on March 6 that "there will be a bunch of work inside the company to make sure that we have the right folks in the right roles" to bring Facebook's apps together and introduce more privacy features.
The departures of Cox and Daniels come a day after a technical issue that limited use of Facebook and Instagram for most of Wednesday. Fidji Simo, vice president of video, games, and monetization, will become the new head of the Facebook app. Daniels led WhatsApp for 10 months, after replacing co-founder Jan Koum, who left the company in April after clashing with Zuckerberg over a plan to loosen privacy and encryption.