Pembrolizumab is used as a tumor-agnostic drug in deficient mismatch repair (dMMR)/microsatellite instability-high (MSI-H) tumors. Jejunal cancer is an uncommon type of gastrointestinal cancer, and mismatch repair deficiency is rare in these tumors. In this study, we presented the first case of dMMR/MSI-H jejunal cancer that progressed rapidly following pembrolizumab treatment. Six courses of adjuvant capecitabine and oxaliplatin were administered to a 58-year-old male patient diagnosed with dMMR/MSI-H T4N2 jejunal adenocarcinoma. To treat the progressive disease, pembrolizumab was initiated, and after two cycles of treatment, diffuse tumoral spread occurred in the bilateral lung and mediastinum. Eight days after the drug was discontinued, the patient died due to respiratory failure. In rare tumors, unresponsive patients are not adequately covered. Administering pembrolizumab may lead to rapid progression of dMMR/MSI-H jejunal cancer.