Doxorubicin is one of the most effective chemotherapy agents widely used in the treatment of various malignancies. However, the use of this drug is associated with several side effects such as cardiotoxicity and disruption of the intestinal microbiome balance. The present study aimed to identify possible relationships between intestinal microorganisms, doxorubicin, and its cardiotoxicity. The relationship between the intestinal microbiome and doxorubicin cardiotoxicity was investigated by extracting and identifying important genes in this process. Gene expression data were first normalized and filtered. Then, the distribution of samples and the separation of genes in different experimental groups were examined through PCA plots. Gene clusters related to each other were identified and a list of genes involved in the doxorubicin-microbiome, doxorubicin-cardiotoxicity, and microbiome-cardiotoxicity relationships was extracted. In the next step, common genes were identified, their interaction network was drawn, and functional enrichment analyses were performed for these genes. According to the results, among the final 24 common genes, the Acta2 gene had a central role in the processes related to microbial dysbiosis and doxorubicin-induced cardiotoxicity. Also, the Ccn2, Col1a1, Col3a1, and Postn genes can promote cellular processes in the heart tissue after doxorubicin administration. This study showed that the Acta2 gene can be studied as a candidate drug target to combat doxorubicin-induced cardiotoxicity. Although these findings are derived from computational analyses, experimental validation in in vitro and in vivo models is required to confirm the results.