Abstract To investigate the protective effects of celastrol on mice with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD), and to explore its underlying mechanism. The levels of low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), total cholesterol (TC), and triglyceride (TG) in serum were tested. Malondialdehyde (MDA) and superoxide dismutase (SOD), GOT, and GPT in serum were also detected. The histopathological changes of liver tissues were observed by HE staining. The apoptosis cell number of liver tissues was measured by TUNEL staining. Nrf‐2 and HO‐1 protein and mRNA expression were evaluated by IHC, WB, and RT‐PCR assay. Celastrol had effects to depress TG, TC, LDL‐C, GPT, GOT, and MDA concentration and increase HDL‐C and SOD concentration (p