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Gasdermin (GSDM)-mediated cell lytic death plays an essential role in immunity and tumorigenesis. Despite the association of gasdermin B (GSDMB) with the tumorigenesis of various cancers, whether GSDMB functions as a prognostic biomarker in renal cell carcinoma remains poorly understood. Here, we explored the potential immunological functions and the prognostic value of GSDMB across multiple tumors with The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, including analyzing the relationship between GSDMB expression and prognosis, tumor–immune system interactions, immunomodulators, and immune cell infiltration of different tumors. Importantly, elevated expression of GSDMB is an essential factor for the poor prognosis of kidney renal clear cell carcinoma (KIRC) patients, suggesting that it might be helpful to predict a survival benefit from a clinical therapy regimen. Furthermore, GSDMB expression promoted the level of CD4+ T-cell infiltration of the tumors but is significantly negatively associated with immature dendritic cells (iDCs) in KIRC. Additionally, we identified TNFRSF25 and TNFSF14 as immunostimulators highly correlated with GSDMB expression. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses showed that GSDMB and its interacting proteins might affect tumor growth through the serine metabolism pathway. Our current results demonstrate a promising therapeutic strategy targeting GSDMB and provide new insights into GSDMB as an immunological and prognostic biomarker for KIRC.