Background/Objectives: Melanoma is an aggressive skin cancer influenced by genetic and immunological factors. The PDCD1 gene encodes PD-1, a receptor involved in immune evasion and therapeutic response. This study aimed to evaluate the association of PDCD1 variants (rs2227982, rs36084323, rs7421861) and its relative gene expression with melanoma in a Mexican population. Methods: An analytical cross-sectional study was conducted with 262 samples: 131 from melanoma patients (newly diagnosed and treatment-naïve) and 131 from cancer-free controls. Genotyping was performed using real-time PCR. PDCD1 expression was assessed by qPCR, normalized with GAPDH, using the 2^−ΔΔCt method and the Pfaffl model. Statistical comparisons included allele/genotype frequencies, expression levels, and clinicopathological associations. Results: No significant association was found between the studied PDCD1 variants and melanoma susceptibility. However, PDCD1 was significantly overexpressed in melanoma samples (2.42-fold increase; p < 0.01), consistent across both quantification methods. Significant associations were also observed between histopathological subtype and Breslow thickness, and between subtype and anatomical site (p < 0.01). Conclusions: Although PDCD1 variants showed no association with melanoma risk, the gene’s overexpression highlights its potential relevance in melanoma immunobiology. These findings contribute to the molecular characterization of melanoma in the Mexican population and support future research on PDCD1 as an immunological biomarker.