No studies have reported the effect of ribosomal protein L22 like 1 (RPL22L1) in lung adenocarcinoma (LUAD). Therefore, we aimed to systematically investigate the role of RPL22L1 in LUAD. The expression of RPL22L1 was analyzed using TCGA, GEO, TIMER, UALCAN databases, and validated by immunohistochemistry (IHC). Gene methylation analysis was performed using the UALCAN, GSCA and MethSurv databases. The immune infiltrates were investigated using the Single Sample Gene Set Enrichment Analysis (ssGSEA), TIMER database, and TISCH database. The results demonstrated that RPL22L1 was up-regulated in LUAD, and verified by IHC. Kaplan-Meier analysis suggested that patients with high RPL22L1 expression had poor prognosis. Multivariate analysis confirmed that RPL22L1 was an independent prognostic factor. Furthermore, RPL22L1 overexpression was associated with hypomethylation, and two CpGs of RPL22L1 were significantly associated with prognosis. Up-regulated RPL22L1 was enriched in MYC targets, E2F targets, G2M checkpoint, mTORC1 signaling, cell cycle, and so on. Moreover, RPL22L1 expression was negatively correlated with immune cell infiltration, and patients with high RPL22L1 expression had lower immune, stromal, and estimate scores. Single-cell analysis suggested that RPL22L1 might have a potential function in the tumor microenvironment (TME) of LUAD. In conclusion, RPL22L1 may be a promising biomarker for LUAD.