Abstract Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to infection. In cases of severe sepsis, the risk of mortality is 40% to 60%. Proinflammatory cytokine levels are elevated in patients causing capillary leakage, coagulation, and organ damage. N, N-dimethylacetamide (DMA) is a widely used drug excipient, which was found to possess anti-inflammatory properties. In this project, we studied the potential effects of DMA in improving sepsis survival and organ damage and in regulating the immune system. To study the potential therapeutic effect of DMA, we utilized an LPS-induced endotoxemia murine model to simulate sepsis-like symptoms. DMA improved 72-hour survival from 17% to 83% in severe endotoxemia. Improved mobility and HR were also observed in DMA treated LPS groups as compared to the LPS only groups. To explore the mechanism of DMA’s ability to improve endotoxemia outcomes, primary murine neutrophils were used. DMA reduced mTNFa levels in primary neutrophils treated with LPS for 24 and 48 hours at 10 mM, the same concentration previously reported to attenuate cytokine secretion in vitro. However, mIL-6 levels were not affected. To further study the effect of DMA on macrophages in vitro, differentiation of human monocyte U937 was induced by PMA. In line with our in vivo and ex vivo studies, U937-macrophages released hIL-6 and hTNFa in response to LPS stimulation while DMA significantly reduced cytokine release when cells were treated with DMA and LPS concomitantly. Additionally, cells co-treated with DMA and PMA during differentiation released less cytokines when compared to the corresponding group treated with PMA only.