Recent studies have demonstrated the role of Nod-like receptor protein 3 (NLRP3) inflammasome in promoting melanoma progression. Immune checkpoint inhibitors (ICI) treatment dramatically extended the survival outcomes for advanced melanoma patients. Nevertheless, immunologic and immunotherapy implications of NLRP3 mutations in melanoma were obscure. Herein, we utilized publicly genomic data of 750 melanoma patients to explore the association of NLRP3 mutations with immunologic and genomic features. In addition, we curated 336 advanced/metastatic melanoma patients treated with ICI agents from 6 published studies to analyze the response rate and survival outcome in relation to NLRP3 mutations. We observed that patients with NLRP3 mutations had a significantly higher tumor mutation burden (P < 0.001) and neoantigen burden (P < 0.001). Moreover, significantly lower tumor heterogeneity (P = 0.048) and purity (P = 0.022) were also observed in this mutated subgroup. Elevated infiltration of immune-response cells, decreased enrichment of immune-suppressive cells, and immune response-related circuits were markedly enriched in patients with NLRP3 mutations. In the pooled ICI-treated cohort, NLRP3 mutations were linked with the higher response rate (P = 0.031) and preferable survival outcome (P = 0.006). NLRP3 mutations were identified to associate with the elevated mutational burden, favorable immune infiltration, and preferable ICI efficacy. Findings derived from our study suggest that NLRP3 mutations may serve as a potential biomarker for evaluating melanoma immunotherapy response.