Objective We constructed a curcumin ( CUR) nanoemulsion drug delivery system to study its protective effect on myocardial ischemia-reperfusion in rats and elucidate the underlying mechanisms. Methods Curcumin nanoemulsions (CUR-NMs) were produced and morphologically characterized by transmission electron microscopy. The rat model of myocardial ischemia-reperfusion was established by ligation of the left anterior descending coronary artery. The rats were randomly divided into sham operation, model, CUR treatment, and CUR-NMs treatment groups. The CUR treatment and CUR-NMs treatment groups were intraperitoneally administered CUR ( 20 mg / kg) and CUR-NMs ( 20 mg / kg) 4 h before ischemia. The hemodynamic changes were detected in each group of rats. TUNEL staining was used to measure the apoptosis of rat myocardial cells. CK, LDH, MDA, and SOD levels were detected using commercial kits. The protein expression of calpain1, calpastatin, Bcl-2, and cleaved-caspase 3 were detected by western blot. Results The prepared CUR-NMs are uniform in size, round in shape, and have a particle size of (121 ± 23) nm. After 30 minutes of ischemia and 2 hours of reperfusion, Left ventricular developmental pressure (LVDP), maximal left ventricular pressure rising rate ( dp / dtmax ), and maximal left ventricular pressure decreasing rate (-dp / dtmax ) indicators in the model group were significantly decreased (P<0. 01), serum LDH, CK, and MDA were significantly increased, and SOD was significantly reduced (P< 0. 01). Compared with the model group, the LVDP, dp / dtmax, and -dp / dtmax of the CUR-treated and CUR- NMs-treated groups were all increased to varying degrees (P< 0. 05 or P< 0. 01), whereas LDH, CK, and MDA were significantly decreased, and SOD was significantly increased ( P < 0. 05 or P< 0. 01). Compared with the CUR-treated group, LVDP, dp / dtmax, and -dp / dtmax increased in the CUR-NMs treatment group (P< 0. 01), serum LDH, CK, and MDA decreased, and SOD increased ( P < 0. 05 or P < 0. 01). Compared with the sham operation group, myocardial apoptosis in the model group was significantly increased (P<0. 01), the expression levels of calpain1 and cleaved-caspase 3 were significantly increased, and the levels of Bcl-2 and calpastatin were significantly reduced (P<0. 01). Compared with the model group, myocardial apoptosis was significantly reduced in the CUR-treated and CUR-NMs-treated groups ( P< 0. 01), the expression levels of calpain1 and cleaved-caspase 3 were significantly reduced, and the levels of Bcl-2 and calpastatin were significantly increased (P<0. 05 or P<0. 01). Compared with the CUR-treated group, myocardial apoptosis was significantly reduced in the CUR-NMs-treated group ( P < 0. 01), calpain1 and cleaved-caspase 3 proteins were downregulated, and Bcl-2 and calpastatin proteins were upregulated (P<0. 05 or P<0. 01). Conclusions CUR-NMs can improve myocardial ischemia-reperfusion injury in rats more effectively than CUR. This effect may be related to enhanced cell uptake or inhibited calpain1 protein expression and activity.