Background Obesity has become a global health concern, with its prevalence steadily rising across populations. Apart from its well-known association with various metabolic disorders, obesity has also been linked to an increased risk of cardiovascular diseases, including myocardial ischemia-reperfusion (IR) injury. This study aimed to assess how irisin and liraglutide, when used together, impact endoplasmic reticulum (ER) stress-induced apoptosis and PI3K/AKT signaling in obese rats after cardiac IR injury. Methods Thirty-six male Sprague-Dawley rats (200-230 g) were fed either a low-fat or high-fat diet for 12 weeks. The obese rats, which were fed a high-fat diet, underwent 30 min of left anterior descending coronary artery occlusion followed by 24 h of reperfusion. Prior to the IR procedure, the obese rats were treated with irisin (0.5 mg/kg/day) and/or liraglutide (0.07 mg/kg/day) for one week. Echocardiographic and hemodynamic parameters, LDH and CK-MB levels, the expression of proteins related to apoptosis (Bax, Bcl-2, cleaved caspase-3) and ER stress (CHOP, GRP78), as well as the phosphorylation of PI3K and AKT, were assessed. Results The combination therapy significantly improved cardiac function and reduced LDH and CK-MB levels (P<.05). Furthermore, this treatment downregulated proteins associated with ER stress, as well as pro-apoptotic markers Bax and cleaved caspase-3, while upregulating the anti-apoptotic protein Bcl-2. Additionally, it enhanced the phosphorylation of PI3K and AKT proteins (P<.05). Conclusion Irisin/liraglutide combination therapy exerted cardioprotective effects against IR injury in obese rats, which were associated with the suppression of ER stress-mediated apoptosis, partly through the enhancement of PI3K/AKT signaling pathway activity.