Calcineurin inhibitor（CNI） is potent immunosuppressive agents and serve as cornerstone therapies in the treatment of organ transplantation and autoimmune diseases， with cyclosporine A and tacrolimus being the representative drugs. Long-term use of CNI can lead to drug-induced hyperglycemia， severely affecting patients’ prognosis. The pathogenesis involves multilevel pathological alterations： at the pancreatic β-cell level， CNI directly damage β-cell by inducing calcium overload， oxidative stress， and mitochondrial dysfunction， suppressing the expression of key insulin synthesis factors and promoting apoptosis； in peripheral tissues， CNI interfere with insulin receptor substrate phosphorylation and inhibit the phosphatidylinositol 3 kinase/protein kinase B signaling pathway， resulting in decreased glucose uptake and insulin resistance； additionally， CNI can also induce β-cell injury by suppressing the secretion and receptor signal transduction of glucagon-like peptide-1， as well as by activating the nuclear factor kappa B pathway to promote inflammatory responses. Clinical studies demonstrate that the incidence of CNI-associated hyperglycemia is closely related to drug type， dosage， and individual patient factors. For high-risk patients， dose adjustment of CNI， switching to agents with lower metabolic toxicity when necessary， and selection of appropriate glucose-lowering regimens based on glycemic levels are recommended. Future research should further elucidate the molecular mechanisms of CNI metabolic toxicity and optimize individualized pharmacotherapy strategies to improve long-term patient outcomes.