This study investigated the mechanism by which Ginseng Radix et Rhizoma-Salviae Miltiorrhizae Radix et Rhizoma (GR-SMR) alleviates doxorubicin (DOX)-induced myocardial injury. Bioactive compound targets were identified using SwissTargetPrediction database, and DOX-induced cardiomyopathy (DIC) targets were screened, bioinformatics platforms and STRING databases analyzed potential GR-SMR targets for DIC treatment, with parallel GO and KEGG enrichment analyses. Finally, H9c2 cells were treated with 2 μmol/L DOX to establish a myocardial injury model for validation, logarithmic growth phase cells into five groups: control group, DOX group, GR-SMR low-dose group (0.5 mg/mL), GR-SMR medium-dose group (1 mg/mL), and GR-SMR high-dose (2 mg/mL), cell viability was assessed using MTT and lactate dehydrogenase (LDH) assays, reactive oxygen species (ROS) production was quantified by flow cytometry, tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6 levels were measured by ELISA. Toll-like receptor 4 (TLR4) and nuclear factor kappa B (NF-κB) mRNA and protein expression were assessed by RT-qPCR and Western blot. Target prediction was performed for 150 active ingredients from GR-SMR, yielding 1 385 targets after duplicate removal, with 578 overlapping DIC targets. KEGG analysis revealed enriched TNF, IL-17, NF-κB and apoptosis pathways. Molecular docking confirmed strong binding affinity between GR-SMR active compounds and TLR4/NF-κB. Experimentally, GR-SMR significantly attenuated DIC and increased cell viability (P < 0.01 or P < 0.001), reduced LDH and ROS (P < 0.01 or P < 0.001), decreased inflammatory factors (P < 0.05 or P < 0.001), and downregulated NF-κB mRNA, TLR4, and p-NF-κB protein expression (P < 0.01 or P < 0.001). Mitochondrial ROS scavenger MitoTEMPO similarly reduced inflammatory factors and p-NF-κB expression (P < 0.01 or P < 0.001), indicating GR-SMR protects against DIC by inhibiting mitochondrial ROS. Therefore, GR-SMR inhibits inflammation and attenuates DOX-induced cardiotoxicity via the TLR4/NF-κB pathway.