Abstract Background The roles and clinical values of synaptojanin 2 (SYNJ2) in lung squamous cell carcinoma (LUSC) remain unclear. Methods A total of 2824 samples from multi-center were collected to identify the expression of SYNJ2 in LUSC by using Wilcoxon rank-sum test, t-test, and standardized mean difference (SMD), and 194 in-house samples were also included to validate SYNJ2 expression in LUSC. The clinical roles of SYNJ2 were investigated via receiver operating characteristic (ROC) curves, univariate Cox regression analysis, and Kaplan–Meier plots. The underlying mechanisms of SYNJ2 in LUSC were explored by gene set enrichment analysis and immune correlation analysis. Further, a pan-cancer analysis based on 10,238 sapiens was performed to promote the understating of the expression and clinical significance of SYNJ2 in multiple human cancers. Results SYNJ2 was found to be significantly upregulated in LUSC at both mRNA and protein levels (p < 0.05, SMD = 0.89 [95% CI 0.34–1.45]) via public and in-house samples. Overexpressed SYNJ2 predicted poor prognosis for LUSC patients (hazard ratio = 2.38 [95% CI 1.42–3.98]). The cancer-promoting effect of SYNJ2 may be related to protein digestion and absorption and extracellular matrix-receptor interaction. SYNJ2 expression was closely related to immune cell infiltration, indicating its role in the immune response. Moreover, the distinct expression levels and essential clinical relevance of SYNJ2 in a series of cancers were initially revealed in this study. Conclusions This study disclosed the clinical significance of SYNJ2 in LUSC and multiple cancers, demonstrating the novel and potential biomarker for predicting and treating cancers.