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Abstract Background The treatment of diffuse large B-cell lymphoma (DLBCL) is limited by the development of resistance to therapy, and there is a need to develop novel therapeutic strategies for relapsed and refractory aggressive lymphoma. Metformin is an oral agent for type 2 diabetes that has been shown to decrease cancer risk and lower mortality in other types of cancer. Methods We performed a retrospective analysis of the RPCCC database looking at patients with DLBCL treated with front-line chemotherapy. We also performed pre-clinical studies looking at the effect of metformin on cell viability, cell number, Ki67, ATP production, apoptosis, ROS production, mitochondrial membrane potential, cell cycle, effect with chemotherapeutic agents, and rituximab. Finally, we studied mouse models to see the anti-tumor effect of metformin. Results Among diabetic patients, metformin use was associated with improved progression-free survival (PFS) and overall survival (OS) compared to diabetic patients not on metformin. Our pre-clinical studies showed metformin is itself capable of anti-tumor effects and causes cell cycle arrest in the G1 phase. Metformin induces apoptosis, ROS production, and increased mitochondrial membrane permeability. Metformin exhibited additive/synergistic effects when combined with traditional chemotherapy or rituximab in vitro. In vivo, metformin in combination with rituximab showed improved survival compared with rituximab monotherapy. Conclusions Our retrospective analysis showed that metformin with front-line chemotherapy in diabetic patients resulted in improved PFS and OS. Our pre-clinical studies demonstrate metformin has potential to re-sensitize resistant lymphoma to the chemo-immunotherapy and allow us to develop a hypothesis as to its activity in DLBCL.