Heat shock protein 22 (HSP22) can reduce type 2 diabetes mellitus (T2DM) induced vascular endothelial injury by inhibition of inflammation and oxidative stress. Therefore, we explored whether HSP22 alleviated diabetes cardiomyopathy (DCM) in mice. A T2DM mouse model was constructed and myocardial tissues were used to perform transcriptome sequencing. HSP22 transgenic and HSP22 knockout mice were established to confirm its role in DCM. Transthoracic echocardiography, hematoxylin-eosin staining, TUNEL staining and apoptosis-related proteins were detected to evaluate myocardial injury. Dihydroethidium staining, malondialdehyde and superoxide dismutase levels were detected to evaluate myocardial oxidative stress. We performed RT-PCR to detect inflammatory factors and evaluate the myocardial inflammatory response. Immunohistochemical staining, RT-PCR and western blot were used to define the expression of HSP22 in mouse myocardial tissues. Transcriptome sequencing analysis revealed the expression of HSP22 in myocardium of T2DM mice significantly decreases. GO analysis found that oxidative stress and inflammatory response were closely related to DCM in mice. Furthermore, HSP22 overexpression can alleviate DCM in mice and HSP22 knockout aggravated DCM. HSP22 reduced oxidative stress and inflammation to alleviate DCM in mice.