The significance of NSUN2 in carcinogenesis is gradually being recognized, yet a comprehensive analysis across pan-cancer remains a pivotal void in existing research. In our investigation, we capitalized on the UCSC Xena platform to evaluate NSUN2 expression levels and their prognostic implications across a range of cancer types. Furthermore, we employed the cBioPortal database to delve into the genomic variations of NSUN2 within human cancers. Our study encompassed the use of molecular docking, genomic tumor profiling, and an assessment of the gene's responsiveness to pharmacological treatments. Additionally, we utilized algorithmic techniques to measure the relationship between NSUN2 expression and key clinical biomarkers, such as microsatellite instability (MSI), tumor mutational burden (TMB), and immune cell infiltration. Our results have established a notable association between NSUN2 and endometrial cancer (UCEC), thereby confirming its clinical significance through an analysis of tumoral expression patterns, mutational spectra, methylation profiles, and drug sensitivity. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were crucial tools in elucidating the biological roles of NSUN2 in endometrial cancer. Consistently, elevated NSUN2 expression was associated with unfavorable clinical outcomes and was primarily observed in the context of genetic amplifications. Across 22 distinct tumor types, our analysis revealed a notable correlation between NSUN2 expression and various metrics related to immune cell infiltration, tumor stroma, and immune scores. Notably, higher levels of NSUN2 expression have been linked to a reduced response to certain chemotherapeutic agents, including PHA-793887. In UCEC, a positive correlation between NSUN2 methylation and gene expression hints at a potential epigenetic regulatory mechanism underlying cancer progression. Our study highlights the potential of NSUN2 as a key oncogene and its promising role as a therapeutic target as well as a prognostic biomarker for endometrial cancer. This underscores its potential importance in predicting responses to immunotherapy.