Sirtuins are NAD+-dependent enzymes, which respond to changes in energy status by conferring post-translational modifications on their targets and altering their activities. Sirtuin 3, 4 and 5 have been reported to localize in the mitochondria and Sirtuin 1 is a nuclear regulator of mitochondrial biogenesis. We found that S. Typhimurium infection strikingly increases Sirtuin 4 (SIRT4) expression. SIRT4 is a multifunctional enzyme targeting the metabolic entry points of the TCA cycle, thereby inhibiting mitochondrial metabolism. We have deciphered that depletion of SIRT4 ameliorated mitochondrial morphology and improved their quality in the infected cells. Furthermore, loss of SIRT4 resulted in reduced inflammation and cell death, which are the hallmarks of S. Typhimurium-induced pathogenicity. Mechanistically, we deciphered that SIRT4 modulates pathogen induced inflammation by regulating the pyruvate dehydrogenase complex and mitochondrial reactive oxygen species. Additionally, Sirt4 KO mice were also characterized by altered inflammatory response to infection. Taken together, our data suggest that SIRT4 plays a key role in S. Typhimurium-induced mitochondrial dysfunction and thereby controls mitochondrial quality and cell-intrinsic immune responses.