Fibrodysplasia ossificans progressiva (FOP) is a genetic disease characterized by extraskeletal heterotopic ossification (HO). The underlying mechanism is the aberrant activation of bone morphogenetic protein (BMP) signaling caused by a point mutation in the gene. Although FOP is an ultra-rare disease, its symptoms severely impair patients' daily activities and quality of life. Furthermore, the HO is also observed in broader clinical contexts, including major surgeries and trauma, highlighting the significance of its study. We have previously reported that rapamycin suppressed Activin-A-triggered progression of cartilage formation in FOP mice. We recently found that the ACVR2B-Fc fusion protein produced by mesenchymal stem/stromal cells derived from induced pluripotent stem cells (iMSCs) attenuates BMP signaling activated by Activin-A and BMP-9 in FOP patient-derived iMSCs. Transplantation of ACVR2B-Fc-producing iMSCs (iMSC) reduces primary HO in FOP mice. In this study, we found that intraperitoneal administration of rapamycin reduced primary HO in a dose-dependent manner in FOP-ACVR1 transgenic mice. A low concentration of rapamycin (0.3 mg/kg, 5 times/wk) efficiently suppressed chondrogenesis. The combination of iMSC transplantation with low concentration of rapamycin significantly reduced primary and recurrent HO. Rapamycin improved cell survival in transplanted iMSC cells by attenuating chemokine secretion, likely resulting in improved ACVR2B-Fc fusion protein production. Our results suggest that combining stem cell therapy and rapamycin can reduce primary HO and surgery-induced HO.