Background <p>Patients receiving doxorubicin (DOX) chemotherapy are susceptible to cardiac and brain tissue damage, with oxidative stress (OS) as the primary mechanism of injury. The purpose of this research is to identify effective agents to reduce the level of DOX-induced OS in the heart and brain through bioinformatics and in vitro.</p> Methods <p>Cardiac transcriptome data (GSE59672) and hippocampal transcriptome data (GSE178812) were downloaded from the Gene Expression Omnibus database. Meanwhile, OS-related genes were retrieved in the GeneCards database. The intersection of differentially expressed genes (DEGs) and OS-related genes in cardiac and brain tissues was identified to screen for differentially expressed OS-related genes (DEOGs). Subsequently, we performed Kyoto Gene and Genome Encyclopedia enrichment, Gene Ontology annotation, and protein-protein interaction network analysis. Using the Connectivity Map (Cmap) database, we predicted the potential drug to reduce the expression of DOX-induced OS in cardiac and brain injury by key genes and validated the therapeutic effect of the drug in vitro.</p> Results <p>A total of 20 DEOGs were identified. The network’s most important modules and central genes (<i>Col1a1</i>, <i>Lox</i>, <i>Col1a2</i>, <i>Ogn</i>, <i>Myoc</i>, <i>Jph2</i>, <i>Casp1</i>, <i>Aldh1a2</i>, <i>Cfh</i>) were screened by the MCODE plugin of Cytoscape software. Using the Cmap database, Canadine was predicted by key genes to reduce DOX-induced OS levels in cardiac and brain tissues. Canadine elevated superoxide dismutase 1 and catalase and reduced Malondialdehyde and reactive oxygen species levels in DOX-treated H9C2 and PC12 cells.</p> Conclusions <p>Our results show that Canadine ameliorates DOX-induced cardiac and brain tissue damage by inhibiting OS.</p>