The aim of this study was to confirm the protective effect of tetrahydropalmatine (THP) against irradiation-induced rat pulmonary endothelial cell apoptosis and to explore the underlying mechanism, with a focus on the calcium-sensing receptor (CaSR)/phospholipase C-gamma 1 (PLC-gamma 1) pathway. We established a model of irradiation-induced primary rat pulmonary endothelial cell injury. Cell apoptosis and mitochondrial membrane potential (Delta psi m) were measured by flow cytometry. The expression of CaSR, cytochrome c, PLC-gamma 1, reactive oxygen species (ROS) and [Ca2+](i) was also determined. Caspase-3 and caspase-9 activities were measured using commercial kits. Inositol triphosphate (IP3) and the production of inflammatory cytokines were detected by enzyme-linked immunosorbent assay. The results showed that THP significantly inhibited irradiation-induced cell apoptosis and intracellular accumulation of ROS. Pretreatment with THP significantly decreased the expression of CaSR, inhibited the CaSR/PLC-gamma 1 pathway and subsequent [Ca2+](i) overload stimulated by irradiation. THP, NPS2390 (inhibitor of CaSR), U73122 (inhibitor of PLC-gamma 1) and 2-APB (inhibitor of IP3) further decreased cell apoptosis, along with down-regulation of cytochrome c, caspase-3 and caspase-9 activation, disruption of Delta psi m and the production of inflammatory cytokines. These findings suggest that THP protects primary rat pulmonary endothelial cells against irradiation-induced apoptosis by inhibiting oxidative stress and the CaSR/PLC-gamma 1 pathway.