Objective: To investigate the protective effect of Yulangsan Chalcone (YLSC) on H9c2 cardiomyocytes hypertrophy induced by angiotensin II (Ang II) and its possible mechanism. Methods: H9c2 cardiomyocytes were divided into blank control group, model group, and low-, medium-, and high-dose groups of YLSC. After intervention with YLSC, the cells were induced to form a hypertrophy injury model with Ang II at a concentration of 1 μmol/L. Cell viability was detected by CCK-8, autophagy of apoptotic substances was detected by MDC staining, ROS levels were detected by DCFH-DA fluorescence probe method, apoptosis was detected by Hoechst 33342 staining, ATP content was detected by ELISA, and the levels of Bnip-3 and Atg5 were detected by RT-PCR. The expressions of autophagy marker proteins p62, Beclin1 and LC3II/LC3I were detected by WB. Results: YLSC can alleviate Ang II-induced H9c2 cardiomyocyte hypertrophy injury. CCK-8 assay indicates that YLSC can enhance the viability of hypertrophic cardiomyocytes. MDC staining method suggests that YLSC can initiate autophagy to clear apoptotic cells. DCFH-DA fluorescence probe method detection results show that YLSC can reduce the generation of reactive oxygen species. Hoechst 33342 staining method detection results show that the test drug can reduce cell apoptosis. ELISA detection results show that the test drug can increase the ATP level of cells. RT-PCR detection results show that the test drug can promote the gene expression of Bnip-3 and Atg5. WB detection results show that YLSC can reduce the expression of p62 and increase the expression of Beclin1 and LC3II/LC3I. Conclusion: YLSC can effectively inhibit Ang II-induced H9c2 cardiomyocyte hypertrophy and apoptosis, and its mechanism may be related to the initiation of myocardial autophagy, activation of autophagy-related factors and clearance of apoptotic cells.