Coagulation factor family genes play a pivotal role in tumor progression and immune modulation, but their relationship with tumor microenvironment and immunotherapy response in gastric cancer remains unclear. This study utilized single-cell and The Cancer Genome Atlas datasets to investigate the clinical and immune relevance of coagulation factor family genes in gastric cancer. Based on coagulation factor family genes, a risk score was constructed. The high-risk group was found to have a worse prognosis and exhibited an immunosuppressive state. Coagulation factor V (F5) emerged as a central gene, correlating negatively with immune cell recruitment and cytotoxic activity within the tumor immune cycle. In vitro knockdown experiments and in vivo 615 mouse liver metastasis models showed that F5 enhances metastasis and reduces CD8+ T cell infiltration. Immunohistochemistry (n = 64) and flow cytometry (n = 31) further confirmed F5 immunomodulatory effects. Among 37 patients receiving neoadjuvant immunotherapy, low F5 expression was associated with improved response. Finally, Gastrodin was identified via virtual screening and molecular dynamics as a potential small-molecule inhibitor of F5. These findings indicate that coagulation factor family genes, particularly F5, promote gastric cancer progression and immune evasion, and that targeting F5 may enhance immunotherapeutic outcomes.