This study was aimed to examine the possible underlying cardioprotective efficacy of tangeretin (TAN) in rats exposed to isoproterenol (ISP). Forty male SD rats were separated into four equal groups as the control group, ISP (myocardial infarction; MI group) group rats which were injected intraperitoneally (ip) with 85 mg/kg of ISP. Treatment TAN groups (TAN 50 and TAN 100) rats were orally pretreated with TAN (50 or 100 mg/kg) for 28 days before ISP exposure. Pretreatment with TAN (50/100) significantly reduced (p < .05/0.01) the infarct size, levels of inflammatory markers, cardiac marker enzymes, apoptotic markers along with improved antioxidants. Histo‐morphological results also well‐supported the results of the above biochemical parameters by displaying normal myofibrillar arrangement in TAN pretreated rats. Moreover, the protein expressions of pPI3K and pAkt were considerably elevated in rats administered with TAN. Collectively, TAN pretreatment (especially TAN 100) display better cardioprotective activity against ISP‐induced MI rats. Practical applications Tangeretin (TAN) has been reported to exhibit an array of biological functions including cardioprotective, hepatoprotective, and renoprotective activities. However, the in‐depth mechanism is still lacking, which results in this study. Our results indicate that TAN could effectively reduce cardiac infarct size, inflammatory markers, oxidative stress, apoptotic markers, by modulating (upregulating) the protein expressions of the PI3K/Akt signaling pathway. Thus, demonstrating that TAN could be a strong contender for developing a cardioprotective agent and can recommend along with conventional cardioprotective drugs for abolishing MI‐related complications/symptoms. Nevertheless, further human studies are needed to confirm the above suggestion.