Rationale: Primary squamous cell carcinoma (SCC) of the pancreas is a rare entity since the pancreas lacks squamous cells. This condition is associated with a poor prognosis, and there is currently no optimal treatment strategy for it. Patient concerns: A 64-year-old female patient with a complaint of epigastric pain for 3 months was referred to our hospital. Diagnoses: She was finally diagnosed with primary SCC of the pancreas with lymph node metastasis on the basis of radiological and pathological findings. Interventions: She received chemoradiation along with targeted therapy and was provided with treatment response evaluation through PET/CT. Outcomes: She eventually died of tumor progression after 8 months. Lessons: Primary SCC of the pancreas is associated with a poor prognosis. Comprehensive therapy and proper radiologic evaluation may facilitate prolonged survival of these patients.