Celebrities like Ariana Grande and Selena Gomez were among the most affected, with Mashable reporting their drops at around two million each.
YouTuber James Charles says he lost up to 500,000 followers.
There was speculation Instagram had just carried out a 'purge' of "inauthentic" followers, but a statement from the Facebook-owned company suggests it could be something else.
Watch out influencers - Instagram is culling your fake followers
"We're aware of an issue that is causing a change in account follower numbers for some people right now," Instagram wrote on its official Twitter account.
"We're working to resolve this as quickly as possible."