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Loss of T‐type calcium channel (TCC) function has been reported to result in decreased cell viability and impaired muscle regeneration, but the underlying mechanisms remain largely unknown. We previously found that expression of TCC is reduced in aged pelvic floor muscle of multiple vaginal delivery mice, and this is related to endoplasmic reticulum stress (ERS) activation and autophagy flux blockade. In the present work, we further investigated the effects of TCC function loss on C2C12 myotubes and skeletal muscle, which is mediated by promotion of ERS and ultimately contributes to mitochondrial‐related apoptotic cell death. We found that application of a TCC inhibitor induced mitochondria‐related apoptosis in a dose‐dependent manner and also reduced mitochondrial transmembrane potential (MMP), induced mito‐ROS generation, and enhanced expression of mitochondrial apoptosis proteins. Functional inhibition of TCC induced ERS, resulting in disorder of Ca2+ homeostasis in endoplasmic reticulum, and ultimately leading to cell apoptosis in C2C12 myotubes. Tibialis anterior muscles of T‐type α1H channel knockout mice displayed a smaller skeletal muscle fiber size and elevated ERS‐mediated apoptosis signaling. Our data point to a novel mechanism whereby TCC blockade leads to ERS activation and terminal mitochondrial‐related apoptotic events in C2C12 myotubes and skeletal muscles. [ABSTRACT FROM AUTHOR]