Aim: The aim of the present systematic review is to evaluate the pain perceived by patients during rapid maxillary expansion (RME) in relation to factors such as demographic characteristics, appliance type, activation protocol, and the eventual use of medication or pain management strategies. Materials and methods: An electronic search of available articles on the subject was conducted on three electronic databases, using predefined keywords. Sequential screenings based on pre-established eligibility criteria were performed. Results: Ten studies were ultimately included in this systematic review. The main data of the reviewed studies were extracted according to the PICOS approach. Conclusions: Pain is a common effect of RME treatment that tends to decrease over time. Gender and age differences in pain perception are not clear. Perceived pain is influenced by the expander design and expansion protocol used. Some pain management strategies can be useful for reducing RME-associated pain.