Purpose <p>Gallbladder squamous cell carcinoma (SCC) is a rare subtype of gallbladder malignancy, comprising only 1–4% of cases. Ectopic expression of β-human chorionic gonadotropin (β-hCG) has been described in various epithelial cancers and is associated with aggressive behavior. We report the first known case of gallbladder SCC with diffuse β-hCG expression and markedly elevated serum β-hCG levels, aiming to explore its clinicopathological implications and potential as a prognostic biomarker.</p> Methods <p>We present the clinical, radiologic, surgical, and pathological findings of a patient with a large gallbladder mass. A literature review was conducted to contextualize our findings.</p> Results <p>The patient underwent open cholecystectomy with hepatic segment IVb/V resection. Final pathology revealed poorly differentiated SCC with acantholytic features and diffuse β-hCG immunoreactivity. Two metastatic lymph nodes were identified in the low hepatoduodenal nodal basin. Postoperative serum β-hCG was significantly elevated. Despite surgical resection, the patient experienced rapid disease recurrence and progression.</p> Conclusion <p>This case represents the first documented instance of β-hCG-expressing gallbladder SCC. Diffuse β-hCG expression may reflect a dedifferentiated and aggressive tumor phenotype associated with early metastasis and poor prognosis. Further studies are warranted to investigate the prognostic and biological significance of β-hCG in gallbladder SCC and its potential role as a biomarker.</p>