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Abstract Background Estrogen receptor beta (ERβ) was considered as a tumor-inhibiting factor in estrogen-sensitive malignant tumors. In this study, we intended to investigate whether ERβ was involved in inducing autophagy in osteosarcoma. Methods This is an experimental study. The associations between ERβ and autophagy were detected in osteosarcoma U2-OS cells which were treated with E2, E2 + 2,3-Bis (4-hydroxyphenyl) propionitrile (DPN, ERβ agonists), E2 + DPN + water, E2 + DPN + 3-Methyladenine (3-MA, autophagy inhibitor), respectively. Cell viability and death were detected using cell counting kit 8 assay and flow cytometry, respectively. In addition, the expression of autophagy marker LC3II/I, sequestosome 1 (P62), mammalian target of rapamycin (mTOR), and phosphorylated-mTOR (p-mTOR) was determined by reverse transcription quantitative polymerase chain reaction (RT-qPCR) and Western blotting. Results Cell viability was significantly decreased with DPN treatment, while was reversed with 3-MA treatment. DPN treatment decreased living cells proportion and increased cell apoptosis proportion, while 3-MA treatment reversed those changes. However, there were significant differences between the E2 group and the E2 + DPN + 3-MA group for the living cell proportion and cell apoptosis proportion, suggesting apoptosis and autophagy all were induced. In addition, DPN treatment upregulated the LC3II/I expression level and downregulated P62 and mTOR (mRNA level) and p-mTOR (protein level) expression levels. Conclusion ERβ inhibited the cell viability and mediated cell death by inducing apoptosis and autophagy in osteosarcoma. ERβ-induced autophagy in osteosarcoma was associated with downregulating the P62 expression level and inhibiting mTOR activation.