Regulator of G protein signaling 12 (RGS12) belongs to the superfamily of RGS proteins defined by a conserved RGS domain that canonically binds and deactivates heterotrimeric G-proteins. As the largest family member, RGS12 is widely expressed in many cells and tissues. In the past few decades, it has been found that RGS12 affects the activity of various cells in the human body, participates in many physiological and pathological processes, and plays an important role in the pathogenesis of many diseases. Here, we set out to comprehensively review the role of RGS12 in human diseases and its mechanisms, highlighting the possibility of RGS12 as a therapeutic target for the treatment of human diseases.