Background and Purpose: We have previously shown that the antidiabetic drug metformin protects hepatocytes against toxicity by various stressors. Chronic or excessive consumption of diclofenac (DF), a pain-relieving drug, leads to drug-induced liver injury via a mechanism involving mitochondrial damage and ultimately apoptotic death of hepatocytes. However, whether metformin protects against DF-induced toxicity is unknown. Recently, we have shown that cAMP elevation is protective against DF-induced apoptotic death in hepatocytes, a protective effect primarily involving the downstream cAMP effector EPAC and preservation of mitochondrial function. This study aimed to investigate whether metformin protects against DF-induced toxicity via cAMP-EPACs. Experimental Approach: Primary rat hepatocytes were exposed to 400 µmol/L DF. CE3F4 or ESI-O5 were used as EPAC-1 or 2 inhibitors, respectively. Apoptosis was measured by caspase-3 activity and necrosis by Sytox green staining. Seahorse X96 assay was used to determine mitochondrial function. Mitochondrial reactive oxygen species (ROS) production was measured using MitoSox, mitochondrial MnSOD expression by immunostaining and mitochondrial morphology (fusion and fission ratio) by 3D refractive index imaging. Key Results: Metformin (1 mmol/L) was protective against DF-induced apoptosis in hepatocytes. This protective effect was EPAC-dependent (mainly EPAC-2). Metformin restored mitochondrial morphology in an EPAC-independent manner. DF-induced mitochondrial dysfunction demonstrated by decreased oxygen consumption rate, increased ROS production, and a reduced MnSOD level were all reversed by metformin in an EPAC-dependent manner. Conclusion and Implications: Metformin protects hepatocytes against DF-induced toxicity via cAMP-dependent EPAC-2. Data available on request from the authors.