There's no official word on what caused the Instagram founders to leave, although rumours hint at clashes between the two men and Facebook executives over diminishing independence and demands to direct more users from Instagram to Facebook.
Instagram founders Mike Krieger, left, and Kevin Systrom attend the 16th annual Webby Awards in NY in 2012.
The departures raise questions about Instagram's future at a time when Facebook faces its most sustained set of crises in its history. Instagram, which now has more than one billion users, is a key driver of revenue for Facebook.
Instagram has been a hit with young internet users, an audience that Facebook is keen to keep in its fold. "I've learned a lot working with them for the past six years and have really enjoyed it".
They added that they were planning to take some time off after they part ways with the company they built, saying they hope to "explore our curiosity and creativity again". Concerns over Facebook's business sparked the biggest one-day wipeout in United States stock market history in July. Since then, Instagram has surged further in popularity, while Snapchat's growth has been inconsistent.
WhatsApp chief executive and co-founder Jan Koum said in April he would quit the popular messaging service he co-founded in 2009 and sold to Facebook in 2014.
Instagram in June announced it passed a billion active users, and unveiled a new long-form video feature in a bid to attract "creators" like those on YouTube.
BBC North America technology reporter Dave Lee said Instagram's popularity has soared in a period where use of the core Facebook product has stagnated.
Instagram has largely escaped Facebook's high-profile problems over user privacy, foreign elections interference and fake news, even though it is not immune to any of these things (Facebook recently disclosed it has deleted hundreds of pages on its namesake site as well as Instagram that were linked to global misinformation campaigns meant to disrupt elections).