<p>Acute pancreatitis (AP) is a common acute and critical disease of the digestive system. The initial step of its pathogenesis is the abnormal activation of trypsinogen within pancreatic acinar cells. Seminal studies have identified autophagy dysfunction as a critical upstream regulatory step in this process. Under physiological conditions, selective autophagy, such as zymophagy, may clear aberrantly activated zymogen particles in the cell and maintain pancreatic homeostasis. However, in AP defective autophagic flux, manifested by a defect in autophagosome-lysosome fusion, decreased lysosomal enzyme activity, and accumulation of microtubule-associated protein light chain 3 II (LC3-II) and sequestosome 1 (p62), induces trypsinogen missorting and premature activation. This starts the pancreatic autodigestion cascade. This results in a vicious cycle of an “autophagy pancreatic enzyme axis” involving the mammalian target of rapamycin (mTOR)/AMP-activated protein kinase (AMPK), nuclear factor kappa B (NF-κB), and reactive oxygen species (ROS) pathways and key regulators such as autophagy-related 16-like protein 1 (ATG16L1), vacuole membrane protein 1 (VMP1), and microRNA 155. Moreover, the mechanism of autophagy dysfunction is heterogeneous among the etiologies of AP, such as biliary, alcoholic, and hyperlipidemic acute pancreatitis. Currently, intervention strategies such as rapamycin, emodin, and miR-155 inhibitors have shown potential in regulating autophagy and reducing pancreatic injury in animal models. However, there are still challenges to clinical translation, including the target specificity, the timing of intervention, and the dual role of autophagy in AP. Future studies should focus on in-depth analysis of the mechanism of key molecules in human pancreatic tissue, development of tissue-specific autophagy regulators, and combining etiology typing and biomarkers to promote individualized treatment strategies of AP.</p>