〔Abstract〕 Objective To investigate the protective effect of hyperoside(Hyp) on transverse aortic constriction-induced cardiac hypertrophy and its possible mechanism. Methods Forty 8-week-old male C57BL/6J mice were randomly divided into four groups: Sham group, TAC group, Hyp+TAC group and Hyp+ML385+TAC group. Four weeks after operation, cardiac function including left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS) and left ventricular end-diastolic posterior wall thickness(LVPWd) were measured with echocardiography. HE staining was used to evaluate the myocyte cross-sectional area. Masson staining was used to determine myocardial fibrosis. The ratio of heart weight/body weight was calculated. DHE staining was used to assess reactive oxygen species(ROS) production. The mRNA levels of atrial natriuretic peptide(ANP), brain natriuretic peptide(BNP) and β-myosin heavy chain(β-MHC) were detected by qRT-PCR. The protein levels of NF-E2-related factor 2(Nrf2), heme oxygenase-1(HO-1), superoxide dismutase2(SOD2) and NADPH-Oxidase 2(gp91phox) were detected by Western blot. Differences among groups were compared by one-way analysis of variance, and LSD-ttest was used for comparison between the two groups. Results Compared with the Sham group, the values of LVEF and LVFS in the TAC group decreased(P<0.01). The value of LVPWd, the cross-sectional area, fibrosis and the ratio of HW/BW increased(P<0.01). The mRNA levels ofANP,BNPandβ-MHCwere upregulated(P<0.01). The ROS production and gp91phox protein level were elevated in the TAC group(P<0.01), while the protein levels of Nrf2, HO-1 and SOD2 decreased(P<0.01). Compared with the TAC group, the values of LVEF and LVFS in the Hyp+TAC group increased(P<0.01). The value of LVPWd, the cross-sectional area, fibrosis and the ratio of HW/BW decreased(P<0.01). The mRNA levels ofANP,BNPandβ-MHCwere downregulated(P<0.01). The ROS production and gp91phox protein levels were reduced in the Hyp+TAC group(P<0.01), while the protein levels of Nrf2, HO-1 and SOD2 increased(P<0.01). However, ML385 could partially reverse the protective effects of Hyp on TAC-induced cardiac hypertrophy. Conclusion Hyp alleviates pressure overload-induced cardiac hypertrophy by inhibiting oxidative stress and fibrosis, and its mechanism may be related to Nrf2/HO-1 signaling.