Cardiac remodelling is a major determinant of heart failure (HF) and is characterised by cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. Hesperetin, which belongs to the flavonoid subgroup of citrus flavonoids, is the main flavonoid in oranges and possesses multiple pharmacological properties. However, its role in cardiac remodelling remains unknown. We determined the effect of hesperetin on cardiac hypertrophy, fibrosis and heart function using an aortic banding (AB) mouse. Male, 8-10-week-old, wild-type C57 mice with or without oral hesperetin administration were subjected to AB or a sham operation. Our data demonstrated that hesperetin protected against cardiac hypertrophy, fibrosis and dysfunction induced by AB, as assessed by heart weigh/body weight, lung weight/body weight, heart weight/tibia length, echocardiographic and haemodynamic parameters, histological analysis, and gene expression of hypertrophic and fibrotic markers. Also, hesperetin attenuated oxidative stress and myocytes apoptosis induced by AB. The inhibitory effect of hesperetin on cardiac remodelling was mediated by blocking PKCα/βII-AKT, JNK and TGFβ1-Smad signalling pathways. In conclusion, we found that the orange flavonoid hesperetin protected against cardiac remodelling induced by pressure overload via inhibiting cardiac hypertrophy, fibrosis, oxidative stress and myocytes apoptosis. These findings suggest a potential therapeutic drug for cardiac remodelling and HF.