Skin cutaneous melanoma (SKCM) accounts for 75% of skin cancer deaths, with incidence rates continuing to rise alarmingly. Therapeutic strategies for advanced melanoma, such as targeted therapies and immunotherapies, are rapidly emerging, but drug resistance and toxicity remain challenges for many patients. The p38 protein kinases coordinate adaptive cellular responses to extracellular stimuli and modulate important processes dysregulated in tumorigenesis, such as proliferation, differentiation and survival. Although p38 signaling is of potential importance in melanoma, the isoform-specific functions of the p38s in SKCM remain unclear. We studied the effects of pharmacologic and RNAi-mediated inhibition of p38 isoforms in human melanoma cell lines A375 and WM164 using colony formation assay. We report that p38α/p38β inhibition with SB203580, pan-p38 inhibition with Compound 62, or a concurrent p38α and p38δ knockdown enhanced colony formation ability in both cell lines, indicating both specific and redundant roles for p38 isoforms in negative regulation of human melanoma cell survival. We also analyzed the gene expression, prognostic value, and clinical correlations of the p38 isoforms in The Cancer Genome Atlas SKCM sample datasets, utilizing GEPIA, LinkedOmics, TIMER, and GSCALite bioinformatic tools. We report that p38γ expression was upregulated, while p38δ was downregulated in SKCM. In addition, a low level of p38δ correlated with worse disease-free survival. These findings support a novel tumor-promoting role for p38γ and confirm a tumor-suppressing role for p38δ. Furthermore, higher p38δ was correlated with increased immune cell infiltration, including CD8+ T cells and dendritic cells, and increased T cell exhaustion, suggesting that targeting p38δ in the SKCM TME may stimulate antitumor immunity. Our study highlights the potential paths for translational research efforts.