Mast cells (MCs), a type of innate immune cells, are widely distributed in various human tissues. They migrate to diverse organs via the blood circulation, exhibiting remarkable tissue heterogeneity. MCs play pivotal roles in regulating local inflammation, immune responses, and mediating signal transduction. Recent studies have delved into the impact of MCs on pain regulation, uncovering their involvement in pain onset and progression through multiple mechanisms. Given the crucial roles of MCs in pain modulation, an in-depth investigation of their mechanisms is of paramount importance for developing effective pain management strategies and improving patients' quality of life. This article aims to provide a comprehensive review of the MCs’ roles in pain, shed light on the underlying mechanisms and signaling pathways involved in pain regulation, thereby contributing to the development of solid theoretical foundations and innovative intervention strategies for future pain therapies targeting mast cells.