It should never happen that we don't have an entry in the map, but Flow doesn't know that. In this case I may even consider adding an invariant, as falsy value here would be a programmer error. But I think it is a better idea to analyze why we have to check this condition.
It seems that we're maintaining two collections reactionUsersSet and reactionsUserInfoMap independently, while they are really closely related. So how about removing reactionUsersSet completely and instead add or delete an entry in reactionsUserInfoMap depending on like / unlike action? So this:

if (messageInfo.action === 'add_reaction') {
  messageReactionUsersSet.add(messageInfo.creator.id);
} else {
  messageReactionUsersSet.delete(messageInfo.creator.id);
}
if (!reactionsUserInfoMap.has(messageInfo.creator.id)) {
  reactionsUserInfoMap.set(messageInfo.creator.id, messageInfo.creator);
}

should be replaced with:

if (messageInfo.action === 'add_reaction') {
  reactionsUserInfoMap.set(messageInfo.creator.id, messageInfo.creator);
} else {
  reactionsUserInfoMap.delete(messageInfo.creator.id);
}

And targetMessageReactionsMap would become new Map<string, Map<string, Map<string, RelativeUserInfo>>>() (we can consider introducing some named types to make this more readable).

What do you think about it?