Magnesium ion (Mg²⁺) is an important divalent cation and plays an essential role in various cellular functions. Therefore, cellular Mg²⁺ concentration is tightly regulated by multiple Mg²⁺ channels/transporters. Mg²⁺ deficiency or abnormal Mg²⁺ metabolism is known to lead to various cardiovascular diseases. Cyclin M2 (CNNM2) is one of the members of Na⁺/Mg²⁺ exchangers, participating in Mg²⁺ reabsorption in kidney tubules. However, the pathophysiological significance of CNNM2 in cardiovascular diseases remains unclear. In this study, we generated CNNM2-deficient mice using CRISPR/Cas9 system. CNNM2-deficient mice, fed with a normal Mg²⁺ diet, exhibited significantly decreased serum Mg²⁺ levels and increased urinary Mg²⁺ excretion compared to wild-type mice. In addition, the systolic blood pressure in CNNM2-deficinet mice was lower than that in wild-type mice. Cardiac functions in CNNM2-deficient mice were normal, but interestingly, the susceptibility to epinephrine/caffeine-induced arrhythmia was enhanced. The enhanced susceptibility to epinephrine/caffeine-induced arrhythmia in CNNM2-defocient mice was alleviated by the treatment with a high Mg²⁺ diet for 4 weeks. These results suggest that CNNM2-deficiency with hypomagnesemia is linked to catecholamine-induced arrhythmias.