We detected the high expression level of SOX21-AS1 in tumor tissues and cell lines through performing qRT-PCR analysis. The prognostic value of SOX21-AS1 was identified. Moreover, the biological effects of SOX21-AS1 on HCC cell activities were evaluated by functional assays, such as MTT, colony formation assay and transwell assay. As a result, silenced SOX21-AS1 suppressed cell proliferation and metastasis, resulted in cell cycle arrest, and induced apoptosis in hepatocellular carcinoma. Mechanically, RIP was conducted to prove that SOX21-AS1 could bind with EZH2. ChIp assay was carried out and manifested that SOX21-AS1 epigenetically silenced p21 via recruiting EZH2 to the promoter of p21. Finally, rescue assays were designed and carefully conducted to investigate whether SOX21-AS1 can interact with p21 to affect hepatocellular carcinoma progression. Kaplan Meier method analyzed that HCC patients with high levels of SOX21-AS1 expression indicated the short survival time in comparison with those with low levels of SOX21-AS1 expression.