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The two microRNAs miR-192 and miR-194 are abundantly expressed in the liver and are considered serum biomarkers of liver injury. However, their role in the development of liver injury has not yet been determined. In this study, we generated miR-192/194 mutant mice and determined the effect of miR-192/194 loss on acetaminophen (APAP)-induced acute liver injury. With genetic depletion of miR-192/194, mutant mice were fertile and normally developed. No spontaneous liver injuries were observed in mutant mice. After APAP administration, mutant mice developed less severe liver damage than control mice. Specifically, mutant mice exhibited significantly lower serum alanine transaminase (ALT) levels and pericentral necrosis/apoptosis than control mice receiving APAP. β-catenin signaling was activated during the early phase of liver injury. Activated β-catenin signaling led to faster cellular proliferation and higher expression of AXIN2 and glutamine synthetases. After partial hepatectomy, the miR-192/194 mutant hepatocytes were more regenerative than control hepatocytes (as shown by BrdU incorporation). Moreover, in vitro experiments indicated that miR-194, but not miR-192, specifically repressed β-catenin signaling, while animal experiments revealed that chemical-mediated knockdown of β-catenin signaling compromised APAP resistance that liver protected from miR-192/194 genetic depletion. Collectively, our data indicated that the loss of miR-194 promoted liver regeneration and protected the liver from APAP-induced injury., (Copyright © 2021 Elsevier Inc. All rights reserved.)