Ubiquitin-specific protease 22 (USP22), a newly discovered member of ubiquitin hydrolase family, exhibits a critical function in cell cycle progression and tumorigenesis. The forkhead box M1 (FoxM1) transcription factor plays a crucial role in cell proliferation, differentiation and transformation. However, the expression and functions of USP22 in pancreatic ductal adenocarcinoma (PDA) and whether FoxM1 is involved in USP22-mediated cell cycle regulation have not been studied. We examined the expression of USP22 and FoxM1 in 136 stage II PDA tissues by immunohistochemistry. Clinical significance was analyzed by multivariate Cox regression analysis, Kaplan-Meier curves and log-rank test. RT-PCR, western blot analysis, luciferase and immunofluorescence assays were used to investigate the molecular function of USP22 and FoxM1 in PDA fresh tissues and cell lines. USP22 and FoxM1 were significantly upregulated in PDA tissues compared with the paired normal carcinoma-adjacent tissues. A statistical correlation was observed between USP22 and FoxM1 expression. The expression of USP/FoxM1 and co-expression of both factors correlated with tumor size, lymph node metastasis and overall survival. Multivariate Cox regression analysis revealed that the expression of USP22/FoxM1, especially the co-expression of both factors, is an independent, unfavorable prognostic factor. USP22 overexpression is accompanied by an increase in FoxM1 expression and USP22 increases FoxM1 expression to promote G1/S transition and cell proliferation through promoting β-catenin nuclear translocation in PDA cell lines. USP22 promotes the G1/S phase transition by upregulating FoxM1 expression via promoting β-catenin nuclear localization. USP22 and FoxM1 may act as prognostic markers and potential targets for PDA.