"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."