The departures happened right after Zuckerberg announced last week that he was revamping the Facebook platform to become more secure.
The two executives leaving Facebook are Chris Cox, chief product officer and one of the social network's highest-ranking executives, and Chris Daniels, head of WhatsApp. WhatsApp co-founder Jan Koum left over disagreements with the Facebook leadership over WhatsApp's privacy and encryption.
The future of Facebook's business will depend more on ephemeral posts, like those in Instagram Stories, Zuckerberg has said.
Cox, 36, has been at Facebook for more than 13 years and he was once described as "Facebook's most important executive not named Mark Zuckerberg".
Will Cathcart, who currently heads the Facebook app, will now lead WhatsApp, while video boss Fidji Simo will take his job.
Chief Product Officer Chris Cox and WhatsApp Vice President Chris Daniels are departing amid Facebook's push to rebuild Facebook with stronger privacy in mind.
"As Mark has outlined, we are turning a new page in our product direction", he wrote. "This will be a big project and we will need leaders who are excited to see the new direction through", he said in a Facebook post on Thursday. Instagram and Messenger heads, Adam Mosseri and Stand Chudnovsky, will also report to Zuckerberg.
Zuckerberg told Wired magazine on 6 March 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 steady loss of executive talent come amid a painful two year period Facebook has been vilified for abusing user privacy and summoned to testify about the prevalence of fake news and risky political ads on its sites. It's a huge job for Zuckerberg and all the leaders of Facebook's apps, so it's not going to be an easy job for anyone involved. He also thanked both executives for all of their contributions and for helping make the company what it is today.
Cox worked on some of Facebook's key products, including the social network's News Feed, and led the product and design teams.
After a trying year that gave the whole world a fundamental lesson in privacy and trust, it will be interesting to see how Zuckerberg proceeds with his privacy-first mission and the merging of all of these core apps into one single product.