ABSTRACT Four new 2,3‐methylenedioxy‐naphthalene derivatives, named ephedplics A–D (1–4), were isolated from the roots of Ephedra sinica Stapf. The structures of compounds 1 – 4 were elucidated through comprehensive analyses of ultraviolet, infrared, high‐resolution electrospray ionization mass spectrometry, and one‐/two‐dimensional nuclear magnetic resonance data. Ephedplics A–D represent newly identified natural derivatives featuring a 2,3‐methylenedioxy‐naphthalene scaffold. Furthermore, the isolated compounds were evaluated for their protective effects against corticosterone‐induced injury in rat pheochromocytoma (PC‐12) cells in vitro. Compounds 2 – 4 exhibited significant neuroprotective activity, potentially by mitigating the decline in mitochondrial membrane potential, reducing Ca 2+ influx into PC‐12 cells, and significantly increasing cell viability while decreasing the apoptosis rate. The results indicate that compounds 1 – 4 are novel and that compounds 2 – 4 may show neuroprotective effects.