Background and Aim: Recent studies have demonstrated that USP22 was overexpressed in digestive system malignancies. However, the association between positive USP22 expression and clinicopathological and prognostic significance remains controversial. Thus, this meta-analysis was conducted to explore the roles of USP22 in digestive system malignancies. Methods: Articles were selected from PubMed, Cochrane Library, Web of Science, EMBASE database, Chinese CNKI, and Chinese WanFang databases. Relationships between USP22 expression, clinicopathological features, and survival rates were calculated. Pooled odds ratios (ORs) and hazard ratios (H Rs) with 95% confidence intervals (Cis) were calculated with STATA14.2. Results: A total of 1,926 patients from 17 articles were enrolled. Positive expression of USP22 was associated with depth of infiltration, tumor size, differentiation, and TNM stage. However, it was not related to gender and age. Positive USP22 expression indicated poor 5-year overall survival rates (disease-specific survival rates) and disease-free survival rates. However, USP22 expression was not related to 3-year overall survival rates and it was not an independent predictive factor for OS in patients with digestive system malignancies. Conclusion: The present meta-analysis indicated that positive USP22 expression was related to depth of infiltration, tumor size, differentiation, and TNM stage in patients with gastrointestinal carcinoma. USP22 may be an unfavorable prognostic biomarker for HCC in a Chinese population. Further research is necessary.