In this study, we aimed to perform a pan-cancer analysis of leucine zipper protein 2 (LUZP2). A standardized TCGA pan-cancer dataset was downloaded. Differential expression, clinical prognosis, genetic mutations, immune infiltration, epigenetic modifications, tumor stemness and heterogeneity were analyzed. We conducted all analyses through software R 3.6.3 and its suitable packages. Compared to normal samples, we observed that the LUZP2 mRNA expression was significantly upregulated in LGG, PRAD, LUSC and downregulated in KIRC and other eleven cancer species patients. In terms of overall survival, low-expression of LUZP2 was significantly associated with poor prognosis in lower grade glioma (LGG), lung squamous cell carcinoma (LUSC), kidney renal clear cell carcinoma (KIRC) and prostate adenocarcinoma (PRAD). For progression-free survival, we observed that downregulation of LUZP2 was significantly related to LGG, KIRC, LUSC, and PRAD. Our results observed negative correlations of the stemness of LGG and PRAD with the mRNA expression of LUZP2, whose downregulation was closely associated with poor prognosis. The mutation frequencies of LGG, PRAD, KIRC, and LUSC were 0.4%, 0.4%, 0.3%, and 2.1%, respectively. We detected that the LUZP2 level was negatively associated with TILs in most cancers, including LGG, LUSC, PRAD, and KIRC, while the LUZP2 methylation showed the opposite results. In conclusion, the results of our initial pan-cancer investigation provided a somewhat thorough understanding of the functions of LUZP2 on KIRC, LGG, PRAD, and LUSC.© 2022. The Author(s).