Background: Gastric cancer (GC) is a common malignancy worldwide, and its development is influenced by genetic, metabolic, and immune microenvironmental factors. Hypothyroidism (HT), characterized by decreased thyroid hormone levels, has been suggested to influence tumor biology, but the molecular mechanisms linking HT to GC remain unclear. Methods: Based on Mendelian randomization (MR) studies identifying HT-related single-nucleotide polymorphisms (SNPs), the study annotated candidate genes using the Ensembl database and analyzed their differential expression in GC and normal tissues using GEPIA2. Functional enrichment analysis was performed using Metascape, and survival analysis was conducted with Kaplan–Meier Plotter. The study further evaluated the immune infiltration and clinicopathological associations of prioritized genes to investigate their potential roles in GC progression and therapeutic implications. Results: Among 121 candidate genes, 24 were differentially expressed in GC. Functional enrichment analysis revealed that these genes participate in cytokine response, angiogenesis, hemostasis, immune cell regulation, and autoimmune disease pathways. Survival analysis highlighted SH2B3 as a pivotal gene whose high expression correlated with poorer overall survival. Immune infiltration analysis revealed that SH2B3 expression positively correlated with CD8⁺ T cells, neutrophils, and cancer-associated fibroblasts, but negatively with myeloid-derived suppressor cells, suggesting a complex role in shaping the tumor immune microenvironment. Clinicopathological analysis demonstrated an increasing SH2B3 expression with tumor stage, grade, T/N/M classification, and copy number alterations. Conclusion: SH2B3 may serve as a key regulator bridging HT and GC by influencing tumor progression and immune microenvironment dynamics. These findings provide novel molecular and immunological insights into the potential protective role of HT in GC and underscore SH2B3 as a promising prognostic biomarker and therapeutic target.