Pancreatic cancer is a malignancy with extremely low five-year survival rate. Pancreatic tumors maintain a high basal level of autophagy for survival and progression. Autophagy dysfunction leads to tumor progression in pancreatic cancer patients. Clinical trials with autophagy inhibitors, including hydroxychloroquine and chloroquine, showed no significant therapeutic benefit as monotherapy. Instead of using chemical inhibitors, microRNA may serve as an alternative approach for autophagy inhibition. In the context of pancreatic cancer, the feasibility of using the microRNA approach to target core autophagy-related genes has been shown, which results in suppression of initiation or flux blockage of autophagy. In addition, autophagy inhibition leads to increased sensitivity of pancreatic tumors to a variety of therapeutic approaches, including radiotherapy, chemotherapy and other targeted agents. Recent studies suggest microRNA-based autophagy inhibition can be a promising and feasible approach for the clinical care of pancreatic cancer patients. Here we reviewed the mechanism of autophagy and recent progress of autophagy inhibition in pancreatic cancer treatment. We particularly focus on the microRNA approach in autophagy inhibition in pancreatic cancer.