Pancreatic cancer (pancreatic ductal adenocarcinoma: PDAC) is one of the most aggressive neoplastic diseases. Metformin use was associated with reduced pancreatic cancer incidence or better survival in diabetics. Metformin has been shown to inhibit PDAC cells survival and growth in vitro and in vivo. However, clinical trials using metformin failed to decrease pancreatic cancer progression in patients, raising important questions about molecular mechanisms that protect tumor cells from the antineoplastic activities of metformin. We confirm that metformin acts through inhibition of mitochondrial complex I, decreasing the NAD+/NADH ratio and that NAD+/NADH homeostasis determines metformin sensitivity in several cancer cell lines. Metabolites that can restore the NAD+/NADH ratio turned PDAC cells resistant to metformin. In addition, metformin treatment of PDAC cell lines induced a compensatory NAMPT expression increasing the pool of cellular NAD+. The NAMPT inhibitor FK866 sensitized PDAC cells to the antiproliferative effects of metformin in vitro and decreased cellular NAD+ pool. Intriguingly, FK866 combined with metformin increased survival in mice bearing KP4 cells xenografts but not in mice with PANC1 xenografts. Transcriptome analysis revealed that the drug combination reactivated genes in the p53 pathway and oxidative stress providing new insights about the mechanisms leading to cancer cell death.