Chemotherapeutic drugs, such as doxorubicin (Dox), are commonly used to treat a variety of malignancies. However, Dox-induced cardiotoxicity limits the drug’s clinical applications. Hence, this study intended to investigate whether diosmin could prevent or limit Dox-induced cardiotoxicity in an animal setting. Thirty-two rats were separated into four distinct groups of controls, those treated with Dox (20 mg/kg, intraperitoneal, i.p.), those treated with diosmin 100 mg plus Dox, and those treated with diosmin 200 mg plus Dox. At the end of the experiment, rats were anesthetized and sacrificed and their blood and hearts were collected. Cardiac toxicity markers were analyzed in the blood, and the heart tissue was analyzed by the biochemical assays MDA, GSH, and CAT, western blot analysis (NF-kB, IL-6, TLR-4, TNF-α, iNOS, and COX-2), and gene expression analysis (β-MHC, BNP). Formalin-fixed tissue was used for histopathological studies. We demonstrated that a Dox insult resulted in increased oxidative stress, inflammation, and hypertrophy as shown by increased MDA levels and reduced GSH content and CAT activity. Furthermore, Dox treatment induced cardiac hypertrophy and damage, as evidenced by the biochemical analysis, ELISA, western blot analysis, and gene expression analysis. However, co-administration of diosmin at both doses, 100 mg and 200 mg, mitigated these alterations. Data derived from the current research revealed that the cardioprotective effect of diosmin was likely due to its ability to mitigate oxidative stress and inflammation. However, further study is required to investigate the protective effects of diosmin against Dox-induced cardiotoxicity.