Hesperidin (HES) is an abundant and economical dietary bioflavonoid, and it has several pharmacological properties such as antioxidant activity and powerful cardiac protection. However, HES protection against cisplatin (CP)-induced cardiotoxicity and its mechanism have not been fully clarified. The current study was performed to further elucidate the mechanism of HES against CP-induced cardiotoxicity. Mice were orally administered HES (100 or 300 mg kg-1 day-1) for 7 consecutive days and then injected intraperitoneally (i.p.) with CP (5 mg kg-1) on days 3 and 6. On day 8, mice were anaesthetised with sodium pentobarbital (50 mg kg-1, i.p.), and blood and heart samples were collected for analysis. HES treatment reduced CP-induced cardiac pathologic damage and leakage of the myocardial markers cardiac troponin I (cTnI), creatine kinase (CK), and lactate dehydrogenase (LDH). HES treatment reduced levels of reactive oxygen species (ROS) and malondialdehyde (MDA), which is an oxidative product, and increased antioxidant marker levels including superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). HES also reduced the CP-induced release of the inflammatory factors tumour necrosis factor (TNF)-α and interleukin (IL)-6. Additionally, HES treatment up-regulated the expression of anti-apoptotic protein Bcl-2 and down-regulated the expression of pro-apoptotic proteins Bax and Caspase-3. HES treatment also improved the expression of pathway proteins p62 and Nrf2 and inhibited the increase in CP-induced Keap1 expression. Thus, HES may provide protection against CP cardiotoxicity through inhibiting oxidative stress, inflammation, and apoptosis, which may contribute to activation of the p62-Keap1-Nrf2 signalling pathway. These findings suggest that HES may be a promising protective agent against CP cardiotoxicity in future anticancer clinical practice.