Type 1 ryanodine receptor (RyR1) plays a key role in Ca²⁺ release from the sarcoplasmic reticulum (SR) during excitation-contraction coupling of skeletal muscle. Genetic mutations in the RyR1 gene are associated with severe muscle disorders, such as malignant hyperthermia (MH) and central core disease. MH is a serious complication resulting from general anesthesia through commonly used inhalational anesthetics, which is a disorder of Ca²⁺-induced Ca²⁺ release (CICR) via RyR1. Thus far, more than 300 mutations in RyR1 gene have been reported in patients with MH. Also it has been suggested that some heat stroke triggered by exercise or environmental heat stress is related to MH mutations in the RyR1 gene. The only drug approved for ameliorating the symptoms of MH is dantrolene, which has been was first developed in 1960s as a muscle relaxant. However, dantrolene has several disadvantages for clinical use: the main disadvantage is its poor water solubility which makes rapid preparation difficult in emergency situations. Here we show that a novel RyR1-selective inhibitor (Compound 1), effectively rescues MH and heat stroke in new mouse model relevant to MH. In addition, Compound 1 has great advantages of highly water solubility compared to dantrolene. Compound 1 has the potential to be a promising new candidate for effective treatment of patients carrying RyR1 mutations.