Background and purpose Hyperglycemia induced oxidative stress and inflammation lead to development of diabetic cardiomyopathy. Diabetic patients are more at risk for myocardial infarction than non-diabetics. The current study has investigated the involvement of PPAR gamma activation in effects of crocin as a natural carotenoid against cardiac infarction in diabetic rats. Materials and methods Diabetes was induced in male Wistar rats by streptozotocin injection (55 mg/kg, i.p) 15 min after the administration of nicotinamide (110 mg/kg). Then saline, crocin (40 mg/kg, orally) and GW9662 (1 mg/kg, as PPAR gamma antagonist) were injected for 4 weeks. Isoprenaline was administrated on the 27th and 28th days to induce infarction. Cardiac injury markers, antioxidant enzymes content, blood glucose level, lipid profile, pro and anti-inflammatory cytokines, and PPAR gamma gene expression were measured. Results GSH, CAT content, CK-MB isoenzyme, LDH level, IL-10 and PPAR gamma gene expression in myocardial tissue were decreased in diabetic rats receiving isoprenaline and inflammatory cytokines TNF alpha and IL-6 and also plasma lipids were increased. Crocin administration significantly ameliorated inflammatory cytokines levels, CK-MB, and LDH contents and also it could enhance antioxidant capacity and PPAR gamma expression. However, GW9662 administration reversed the effects of crocin. Conclusion Overexpression of PPAR gamma in crocin treated rats and inhibition of crocin effects by GW9662 reflected the potential involvement of PPAR gamma pathway in the protective effects of crocin.