Objective To observe and explore the effect of ruscogenin (Rus) on doxorubicin (DOX)-induced cardiomyopathy in mice and its probable mechanism with a view of providing clinical proof for the prevention and treatment of DOX-induced cardiotoxicity.Methods A single intraperitoneal injection of DOX (15 mg/kg) was performed to construct a mouse model of acute DOX-induced cardiotoxicity. Using random number table, 32 male C57BL/6 mice (8-10 weeks) were divided into Sham group, Rus group, DOX group, DOX+Rus group (n=8/group). The DOX group and the DOX+Rus group were given DOX(15 mg/kg) injection, and from the day of DOX injection, the Rus group and the DOX+Rus group were given additional Rus 10 mg/(kg·d) for 7 consecutive days. At day 7, echocardiography was performed to evaluate the cardiac function, including ejection fraction (EF), fraction shortening (FS), left ventricular end-diastolic dimension (LVEDD), left ventricular end-systolic dimension (LVESD), and heart rate. qRT-PCR was done to detect the expression levels of pyrolysis markers Caspase 1, interleukin-1β(IL-1β), and IL-18. Western blotting was performed to detect the expression of apoptosis-related protein, NO-like-binding domain-like receptor protein 3 (NLRP3) inflammatory body-related protein and p38 mitogen-activated protein kinase (p38MAPK) related protein in cardiac tissue. SPSS statistics 22.0 was used for statistical analysis. One-way ANOVA was performed for data comparison.Results Compared with the Sham group, the DOX group had significantly lower EF and FS level but significantly higher LVEDD and LVESD, Bax/Bcl-2 ratio, NLRP3 and ASC expression, mRNA expression of Caspase 1, IL-1β and IL-18, and phosphorylation level of P-p38 (P<0.05 for all). Compared with the DOX group, the DOX+Rus group had significantly better cardiac function, decreased myocyte pyrolysis (P<0.05), decreased expression level of NLRP3 and P-p38 (P<0.05 for both), and no significant difference in ASC expression level (P>0.05). Conclusion Ruscogenin can improve the cardiac function of mice with DOX-induced cardiomyopathy by inhibiting the NLRP3 inflammasome and p38MAPK pathway.