Near-infrared fluorescence (NIRF) imaging has emerged as a valuable tool in the diagnosis and treatment of hepato-bilio-pancreatic cancers. In liver cancer, NIRF imaging is instrumental in assessing liver functional reserve, which is crucial for determining the feasibility of surgical resection. It also enhances the accuracy of tumor localization during surgery, improving the precision of resection margins. In cholangiocarcinoma and gallbladder cancer, NIRF imaging facilitates better visualization of bile ducts and tumors, aiding in early diagnosis and more effective surgical interventions. Pancreatic cancer presents a unique challenge due to its often late-stage diagnosis; however, next-generation molecular probes used in NIRF imaging show promise for real-time intraoperative visualization, potentially improving the outcomes of surgical resection. The ongoing development of molecular probes specific to pancreatic tumor markers may revolutionize surgical management by allowing for precise differentiation between healthy and cancerous tissues. Collectively, NIRF imaging is transforming the surgical approach to hepato-bilio-pancreatic cancers by increasing the accuracy of tumor detection, guiding resections, and offering potential for better patient outcomes.