<p>Pancreatic metastasis is uncommon and difficult to distinguish from primary pancreatic cancer based on imaging alone, although accurate diagnosis is essential because treatment strategies differ by tumor origin. Endoscopic ultrasound–guided tissue acquisition (EUS-TA) has become an important diagnostic tool, and molecular profiling may identify therapeutic opportunities. A man in his 60s presented with cerebellar masses, and positron emission tomography–computed tomography (PET-CT) revealed hypermetabolic lesions in the rectum and pancreas. Histopathological and molecular analyses confirmed HER2-positive and RAS/BRAF wild-type rectal adenocarcinoma. The pancreatic lesion was complicated by obstructive pancreatitis and an infectious pancreatic pseudocyst. EUS-TA of the pancreatic mass demonstrated metastatic colorectal adenocarcinoma, consistent with pancreatic metastasis from rectal cancer. Following infection control with antibiotics, cytotoxic chemotherapy was considered high risk; therefore, dual HER2-targeted therapy with trastuzumab plus pertuzumab was initiated. After four cycles, tumor marker levels decreased, and radiologic regression of the pancreatic metastasis with improvement of the pseudocyst was observed. This case highlights the diagnostic value of EUS-TA in differentiating pancreatic metastasis from primary pancreatic cancer and suggests that HER2-targeted therapy may be a safe and effective option for HER2-positive metastatic colorectal cancer in situations where cytotoxic chemotherapy is contraindicated because of infectious complications.</p>