Pancreatic cystic lesions (PCLs) are known precursors to pancreatic cancer, one of the deadliest types of cancer worldwide. Surgical removal or pancreatectomies remain the central approach to managing precancerous high-risk PCLs. Endoscopic ultrasound (EUS)-guided therapeutic management of PCLs is a novel management strategy for patients with prohibitive surgical risks. Various ablation techniques have been explored in previous studies utilizing EUS-guided fine needle injection (FNI) of alcohol and chemotherapeutic agents. This review article focuses on EUS-FNI and chemoablation, encompassing the evolution of chemoablation, pancreatic cyst selection, chemotherapy drug selection, including novel agents, and a discussion of its safety and efficacy.