Uveal and skin melanoma are two distinct tumor types arising from melanocytes, cells producing melanin pigment. Despite their common cell of origin, different exogenous and endogenous factors lead to specific mutational patterns known as mutational signatures. This research aims to characterize and compare the mutations and mutational signatures in uveal and skin melanoma, focusing on the mutations in the biomarker genes. The analysis examined the whole exome sequencing data of 80 uveal melanoma patients and 468 skin melanoma patients, publicly available in the TCGA database. Mutational signatures were called using the COSMIC signature refitting method. Fisher’s test was applied to analyze the differentially mutated genes and biomarkers between the melanomas, and the Mann-Whitney U test and one-tailed One-Proportion Z-Test to test the correlation between the specific mutational signatures and biomarker mutations. The results indicate differential mutational profiles of the melanomas, as well as differential mutational processes involved in melanoma mutagenesis. While UV mutational signatures (SBS7b and SBS7a) are predominant in skin melanoma, they are poorly represented in uveal melanoma. UV radiation seems to be responsible for driver mutations in the BRAF, NRAS, and CDKN2A biomarkers in skin melanoma, while other mutational processes are responsible for mutagenesis of uveal melanoma biomarkers, such as aristolochic acid signature SBS22 for GNA11 mutagenesis.