DEAH-box helicase 33 (DHX33) is a potent oncogenic agent on patients with hepatocellular carcinoma and colon cancer. Nevertheless, the prognostic significance of DHX33 in human pan-cancers remains unclear. Various bioinformatics tools have been used to clarify the oncogenic effects of DHX33 in pan-cancers. The Cancer Genome Atlas (TCGA) and Human Protein Atlas (HPA) were used to evaluate DHX33 at the mRNA and protein levels, respectively. The pan-cancer prognostic prediction value of DHX33 was evaluated using the Kaplan-Meier plotter. The association between DHX33 levels and clinicopathological features was then determined using the UALCAN database. In addition, gene set enrichment analysis and nomogram prediction models were constructed. The association between DHX33 levels and immune cell infiltration was then assessed using TISIDB. We determined that DHX33 is aberrantly overexpressed in pan-cancers and related to lung adenocarcinoma (LUAD) clinical stage (p < .001). Moreover, DHX33 overexpression was indicative of poor overall survival, disease-free survival, and progression-free interval in patients with LUAD (p < .05). Furthermore, DHX33 levels were associated with age, N stage, T stage, and pathologic stage in patients with LUAD (p < .001). Additionally, multivariate Cox analysis revealed that DHX33 was an independent risk factor for OS in patients with LUAD. A nomogram model between DHX33 levels and characteristic clinical parameters was developed. Additionally, DHX33 levels correlated with immunomodulators and chemokines. Finally, gene set enrichment analysis revealed that the amyloid fiber formation pathway and the WICH complex positively regulates RNA expression pathway, which was the most enriched in LUAD. Our data revealed oncogenic effects of DHX33 in various cancers. We suggest that DHX33 may serve as a biomarker for poor prognosis in LUAD.© 2023 Wiley Periodicals LLC.