Background and Objective: Heart attack or myocardial infarction (MI) is a serious global issue due to the high mortality rate than other heart diseases. The current animal study was framed to examine whether hispidulin (HIS) exhibit cardioprotective activity in isoproterenol (ISO) induced rat model. Materials and Methods: Totally forty Wistar male rats were segregated into four different groups. Control rats were administered with saline, Hispidulin (HIS) group rats were intraperitoneally injected with HIS (50 mg kg(-1) b.wt.) for 28 days, MI induced group (ISO) rats were injected with 100 mg kg(-1) of ISO for last 2 days. Whereas, HIS and ISO-induced rats (HIS+ISO) group rats were injected with HIS (50 mg kg(-1), i.p.) for 28 days and exposed to ISO (100 mg kg(-1)). Results: Rats injected with ISO significantly increased the heart to body weight ratio, heart weight, cardiac diagnostic markers (LDH, cTnC, CPK), lipid peroxidation products, lipid profile (TC, TG and LDL-c), inflammatory markers as compared with control rats. However, rats pre-treated with HIS for 28 days considerably abolished those elevation caused by ISO induction and revert all the biochemical values to near normal. A marked upregulation in the protein expression of NF-kappa B p65 subunits and TNF-alpha were noted in ISO-induced (MI) group. But on supplementation with HIS the levels of protein expression of NF-kappa B p65 subunits and TNF-alpha were exponentially downregulated. Conclusion: The outcome of this study implied that HIS possess potent cardioprotective activity against ISO-induced MI model by enhancing the oxidative status and suppressing hyperlipidemia and inflammatory response.