Abstract: Objective: To observe the cardioprotective effect of Panax notoginseng saponins myocardial targeting liposomes (PAC-L-PNS) on mice with endotoxemic myocardial injury and explore the possible mechanism. Methods: Fifty male C57BL/6J mice were randomly divided into normal, model, PAC-L-PNS, normal liposomes of PNS (L-PNS) and PNS groups, with 10 mice in each group. The PAC-L-PNS, L-PNS and PNS groups were injected with corresponding drugs in the tail vein, respectively. The mice in the normal and model groups were injected with the same volume of blank liposomes in the tail vein for 5 days, and 4 h after the last dose, mice in the normal group were intraperitoneally injected with saline, and mice in the other groups were intraperitoneally injected with lipopolysaccharide (LPS, 10 mg/kg) to establish a myocardial injury model. Mice were executed 12 hours after modeling, TUNEL staining and HE staining were used to observe the apoptosis of cardiomyocytes and histopathological changes of myocardium in each group; the activities of creatine kinase (CK) and lactate dehydrogenase (LDH) in serum were detected by detector; the contents of IL-6, IL-1β, TNF-α and MCP-1 in serum were detected by enzyme-linked immunosorbent assay (ELISA); the mRNA expression of NF-κB P65, IκBα, TLR4 and IRAK1 in mouse myocardial tissues were determined by reverse transcription-quantitative polymerase chain reaction (RT-qPCR); in addition, vascular irritation and hemolytic assays were performed to preliminarily evaluate the safety of PAC-L-PNS. Results: PAC-L-PNS was virtually free of hemolytic and vascular irritation phenomena and was biocompatible. Compared with the normal group, the apoptosis rate of cardiomyocytes was significantly higher in the model group mice (P＜0.01), and myocardial tissue injury was more severe. Compared with the model group, mice in the PAC-L-PNS and L-PNS groups had significantly fewer myocardial apoptotic cells (P＜0.01) and improved histopathology, and there was no significant difference in mice in the PNS group. Compared with the normal group, CK, LDH activity, IL-6, IL-1β, TNF-α, and MCP-1 content, TLR4, IRAK1, NF-κB P65, and IκBα mRNA expression were significantly elevated in mice in the model group (P＜0.01). Compared with the model group, CK, LDH activity, content of each inflammatory factor, TLR4, IRAK1, NF-κB P65, and IκBα mRNA expression were significantly lower in mice in the PAC-L-PNS group (all P＜0.05). CK activity, content of each inflammatory factor, TLR4, and IRAK1 mRNA expression were significantly decreased in the PAC-L-PNS group compared with the L-PNS and PNS groups (all P＜0.05). Conclusion: PAC-L-PNS has a significant protective effect on LPS-induced endotoxemic myocardial injury, and its mechanism may be related to the inhibition of inflammatory factor production and attenuation of cardiac tissue lesions.