Objective <p>To elucidate the therapeutic effect and mechanism of Compound Danshen Dripping Pill (CDDP) on cardiotoxicity caused by doxorubicin (DOX) and trastuzumab (TRZ)</p> Methods <p>Eighteen Sprague-Dawley (SD) rats were randomly divided into the normal group (normal saline), the model group (DOX/TRZ), and CDDP administration group (DOX/TRZ+CDDP), by a random number table, with 6 rats in each group. Rats’ were administered either DOX or saline via tail vein injection 6 times over an 11-day period. One week later, they received either TRZ or saline via intraperitoneal injection 6 times over another 11-day period. All rats received CDDP or saline via oral gavage continuously for 36 days. Then, echocardiography was performed on the rats, and biochemical parameters of blood and heart samples were determined. Rats’ feces were taken for intestinal flora testing and plasma metabolites were analyzed using untargeted metabolomics.</p> Results <p>Echocardiographic assessment in rats demonstrated that DOX/TRZ induced cardiac dysfunction, whereas CDDP significantly ameliorated this impairment (<i>P</i>&lt;0.05 or <i>P</i>&lt;0.01). Furthermore, results revealed that DOX/TRZ elevated cardiac injury indicators (left ventricular ejection fraction, fractional shortening, cardiac troponin I, creatine kinase, creatine kinase-MB), while CDDP treatment significantly reduced these levels (<i>P</i>&lt;0.05 or <i>P</i>&lt;0.01). Plasma metabolite analysis revealed enrichment in tryptophan metabolism, tricarboxylic acid cycle, and phenylalanine metabolism. Intestinal microbiota analysis showed increased richness and altered abundance of certain bacteria (<i>Clostridia_UCG-014</i> and <i>Lactobacillus</i>) with CDDP treatment.</p> Conclusions <p>CDDP can prevent and protect against DOX/TRZ-induced cardiac injury. It influences tryptophan metabolism by modulating <i>Clostridia_UCG-014</i> abundance, inhibits indole-3-carboxylic acid levels, increases kynurenine levels, thereby exerting anti-cardiotoxic effects.</p>