Pancreatic cancer is one of the leading causes of cancer deaths, and many patients, with advanced disease, suffer from severe pain that can heavily affect their quality of life. In patients with advanced disease, an eminent role is played by percutaneous techniques, which cause tumor necrosis with a minimally invasive approach. High-intensity focused ultrasound (HIFU) is a relatively recent noninvasive technique that allows ablation of different solid tumors including uterine fibroids, and hepatic, renal, and pancreatic tumors. HIFU technology is based on external emission of an ultrasound beam, which has larger amplitudes than the regular diagnostic probes, focused on a precise target, allowing mechanical energy transfer through the tissues and tumor ablation due to thermal and nonthermal effects. Multiple clinical trials have been performed to evaluate the safety, feasibility, and efficacy of HIFU for the palliation of pancreatic tumors, alone or in combination with chemotherapy. Tumor-related pain relief was achieved in the vast majority of reported cases, and no significant side effects were recorded. This review aims to provide a description of HIFU physical principles, briefly summarize the clinical experience, to date, in HIFU treatment of pancreatic cancer, and discuss the possible future challenges, limitations, and insights in HIFU and pancreatic cancer management.