Abstract Background Hepatocellular carcinoma (HCC) is the sixth most prevalent cancer globally and the third leading cause of cancer-related mortality. Protein ubiquitination and deubiquitination play vital roles in human cancers. Ubiquitin-specific protease 13 (USP13) is a deubiquitinating enzyme (DUB) that is involved in many cellular processes. However, the mechanism by which USP13 regulates deubiquitination remains largely unknown. Methods Clinical data were analyzed via online databases. USP13 expression in HCC cell lines and tissues was analyzed via western blotting and immunohistochemistry. A lentivirus was used to established stable USP13-knockdown and USP13-overexpression cells. Cell Counting Kit-8, colony formation, wound healing, Transwell, and sphere formation assays were used to detect the malignant behaviors of HCC cells in vitro. A subcutaneous mouse model was used to investigate the function of USP13 in vivo. Co-immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter assays were conducted to explore the molecular regulation. Results USP13 was upregulated in HCC cell lines and tissues, which predicted a poor prognosis in patients with HCC. Functional experiments in which USP13 was overexpressed or depleted revealed the oncogenic role of USP13 in driving HCC progression both in vitro and in vivo. Mechanistically, WW domain–containing ubiquitin E3 ligase 1 (WWP1) was identified as a binding protein of USP13. Furthermore, USP13 can interact with WWP1 and then remove the K29- and K48-linked polyubiquitination chains from WWP1 to stabilize the WWP1 protein via the ubiquitin–proteasome pathway. Moreover, Yin Yang 1 (YY1) was explored as a new transcription factor of USP13, and YY1 could also upregulate WWP1 expression through USP13. Moreover, YY1 and WWP1 were shown to participate in the oncogenic role of USP13. Conclusions Our findings revealed the functional YY1/USP13/WWP1 signaling axis in HCC, identifying a promising therapeutic target for anti-HCC treatment. Graphical Abstract