Aims Fibroblast growth factor 21 (FGF21) acts as a metabolic regulator and exerts cardioprotective effects. However, the effects of long‐term FGF21 administration on the heart under the FGF21‐resistant condition in obese, insulin‐resistant rats have not been investigated. We hypothesized that long‐term FGF21 administration reduces FGF21 resistance and insulin resistance and attenuates cardiac dysfunction in obese, insulin‐resistant rats. Methods Eighteen rats were fed on either a normal diet (n = 6) or a high‐fat diet (HFD; n = 12) for 12 weeks. Then, rats in the HFD group were divided into two subgroups (n = 6 per subgroup) and received either the vehicle (HFV) or recombinant human FGF21 (rhFGF21, 0.1 mg kg−1 day−1; HFF) injected intraperitoneally for 28 days. The metabolic parameters, inflammation, malondialdehyde (MDA), heart rate variability (HRV), left ventricular (LV) function, cardiac mitochondrial redox homoeostasis, cardiac mitochondrial fatty acid β‐oxidation (FAO) and anti‐apoptotic signalling pathways were determined. Results HFV rats had increased dyslipidaemia, insulin resistance, plasma FGF21 levels, TNF‐α, adiponectin and MDA, depressed HRV, and impaired LV and mitochondrial function. HFV rats also had decreased cardiac Bcl‐2, cardiac PGC‐1α and CPT‐1 protein expression. However, FGF21 restored metabolic parameters, decreased TNF‐α and MDA, increased serum adiponectin, and improved HRV, cardiac mitochondrial and LV function in HFF rats. Moreover, HFF rats had increased cardiac Bcl‐2, cardiac PGC‐1α and CPT‐1 protein expression. Conclusion Long‐term FGF21 therapy attenuates FGF21 resistance and insulin resistance and exerts cardioprotection by improving cardiometabolic regulation via activating anti‐apoptotic and cardiac mitochondrial FAO signalling pathways in obese, insulin‐resistant rats.