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"When you have powerful personalities who really are at war in terms of just ethos, in terms of culture, ... there's going to be a push-comes-to-shove moment," Cramer said Tuesday on "Squawk of the Street. "
"The side that lost is the side of creativity," said Cramer, whose charitable trust owns Facebook shares.
The stock price was down 1.8 percent Tuesday, a day after Instagram announced the departures of Kevin Systrom and Mike Krieger.
Systrom said he and Krieger plan to take time off and explore "our curiosity and creativity again." Zuckerberg praised the Instagram founders in a statement.
Cramer described Systrom and Krieger as the "heart and soul of Instagram," which he said "saved Facebook from complete oblivion."
Instagram has more than 1 billion monthly active users, and is expected to generate about $7.5 billion of sales for Facebook this year, according to J.P. Morgan analyst Doug Anmuth.
On Tuesday, J.P. Morgan predicted Facebook shares were likely to fall significantly in the short term due to the departure of the two key executives.
"Krieger and Systrom represented much more of a free spirit," said Cramer, the host of "Mad Money." "They were not about selling their names. They were not trying to figure out how to capitalize off each person. They were about telling stories. That's what we thought Zuckerberg was about."
Cramer has been critical of Facebook ever since reports on March 17 that Cambridge Analytica had harvested the data from more than 50 million users of the social network without their permission.
At the time, Cramer said Zuckerberg and Facebook COO Sheryl Sandberg were notably silent, and said Facebook should hire a special counsel to show it has nothing to hide.