Objective To investigate the effect and molecular mechanism of taxifolin (TAX) on myocardial hypertrophy in spontaneously hypertensive rats (SHRs). Methods Twenty-four SHRs were divided into an SHR control group (SHR group), TAX group (20 mg/ kg), and TAX+PERK activator CCT020312 (CCT) group (20 mg/ kg TAX+2 mg/ kg CCT) with eight SHRs per group. Eight Wistar-Kyoto (WKY) rats with normal blood pressure were used as the normal control group ( WKY group). All animals were administered corresponding drugs for 8 weeks of continuous treatment. During the experiment, changes in blood pressure were observed. After the treatments, the thickness of the diastolic ventricular septum (IVSd), the thickness of the systolic ventricular septum (IVSs), and the left ventricular ejection fraction (LVEF) were measured by echocardiography to determine the degree of myocardial hypertrophy and cardiac functions. The cardiac index and left ventricular index were calculated. Hematoxylin-eosin (HE), wheat germ agglutinin (WGA), and Masson staining were performed to evaluate pathological changes of myocardial tissue. Real-time quantitative PCR (qRT-PCR) was performed to measure the mRNA expression of atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), type I collagen α1 chain (COL1A1), and type Ⅲ collagen α1 chain (COL3A1) in myocardial tissues. Western blot was performed to detect expression of protein kinase R-like endoplasmic reticulum kinase (PERK)-activator of transcription 4 (ATF4) pathway-related proteins in cardiac muscle. Results After the treatments, compared with the WKY group, systolic blood pressure (SBP), diastolic blood pressure (DBP), IVSd, IVSs, cardiac index, left ventricular index, myocardial cell cross-sectional area, collagen volume fraction (CVF), myocardial tissue ANP, BNP, COL1A1 and COL3A1 mRNA expression, glucose-regulated protein 78 (GRP78), ATF4, and C/ EBP homologous protein (CHOP) protein levels and the p-PERK/ PERK ratio were increased in the SHR group (all P<0. 05), and LVEF was decreased (P<0. 05). Compared with the SHR group, SBP, DBP, IVSd, IVSs, cardiac index, left ventricular index, myocardial cell cross-sectional area, CVF, myocardial tissue ANP, BNP, COL1A1, and COL3A1 mRNA expression, GRP78, ATF4, CHOP protein levels, and the p-PERK/ PERK ratio were decreased in the TAX group (all P<0. 05), and LVEF was increased (P<0. 05). CCT020312 partially reversed the protective effects of TAX on cardiac functions and hypertrophy. Conclusions TAX improves hypertensive myocardial hypertrophy by inhibiting endoplasmic reticulum stress, and its mechanism may be related to inhibiting the PERK-ATF4 pathway.