Chief executive Kevin Systrom said in a statement that he and Mike Krieger, Instagram's chief technical officer, planned to leave the company in the next few weeks and take time off "to explore our curiosity and creativity again".
Instagram founders Mike Krieger, left, and Kevin Systrom attend the 16th annual Webby Awards in NY in 2012.
There was no immediate word on why they chose to leave the company but Mr. Systrom says they plan to take time off to explore their creativity again. They founded the photo-sharing app in 2010 and sold it to Facebook in 2012 for about $1 billion.
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For much of the past two years, Facebook has been criticized for its handling of user data and also for not preventing foreign interference.
A spokeswoman for Facebook, which owns Instagram, did not immediately have a comment.
Any significant changes to Instagram could hurt Facebook's bottom line as, unlike its parent company, the network has retained its popularity during the scandals. Building new things requires that we step back, understand what inspires us and match that with what the world needs; that's what we plan to do.
In a statement, Zuckerberg described the two as "extraordinary product leaders".
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Facebook's stock hasn't recovered from the hit, either. The social media giant's shares posted the biggest one-day stock-market wipeout in American history in July after sales and user growth disappointed investors. All the other companies in the FAANG group are up this year.
Increased advertising on Instagram has seen the average price-per-ad across Facebook's apps decline this year after a year of upswing.
Camera IconStanford University graduates and founders of Instagram, Kevin Systrom and Mike Krieger.Picture: Supplied, Instagram. Earlier this year, Adam Mosseri, who formerly ran Facebook's news feed, was brought to Instagram to be head of product.
As Facebook saw a threat in young people departing the network for Snapchat, a rival photo-sharing network, Instagram was quick to shift and recreate one of Snapchat's key features of online stories.
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WhatsApp co-founder Jan Koum earlier this year left Facebook, which bought the smartphone messaging service for $19 billion.