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Tuberculosis (TB) caused by Mycobacterium tuberculosis (Mtb) has an alarming mortality rate, and the fast-growing drug resistance of Mtb necessitates the discovery and application of new therapeutic agents. Although Sirt1 is a key regulator in metabolic, cardiovascular and other age-related diseases, its role in the regulation of antibacterial immunity is unclear. Here, we have reported that Sirt1 expression was decreased, and the decreased Sirt1 level was correlated with increased pro-flammatory cytokines and TAK1 phosphorylation in active TB patients. Our mechanistic experiments showed that Sirt1 direclty interacted with TAK1 and suppressed its activation. Further, Sirt1+/− macrophages infected with Mtb exhibited enhanced activation of TAK1, MAPKs and NF-κB, as well as simultaneously elevated expression of pro-inflammatory cytokines. Moreover, Sirt1+/− mice exhibited overt inflammation, as indicated by the significant abundance of pro-inflammatory cytokines, and were more susceptible to Mtb infection than wild-type mice. Overall, the findings indicate that inhibition of Sirt1 expression by Mtb infection enhances TAK1 activation, and this in turn enhances the secretion of IL-6 and TNF-α via activation of the p65/p38/JNK/ERK signaling pathways. Treatment with resveratrol, which is known that one of its multiple effects is Sirt1 activation, in Mtb -infected macrophages inhibited the activation of TAK1, MAPK and NF-κB pathways, and the pro-inflammatory cytokine levels. Consitently, mice treated with resveratrol were more resistant to Mtb infection. The potent therapeutic effects of resveratrol against Mtb infection indicate that Sirt1 could be a novel therapeutic target for the treatment of TB. • Sirt1 expression was low in PBMCs from clinical TB samples and Mtb -infected murine peritoneal macrophages. • Sirt1 interacted with TAK1 and inhibited its phosphorylation and ubiquitination. • Sirt1+/− mice were more susceptible to Mtb infection than WT mice. • Resveratrol alleviated Mtb infection through anti-inflammatory mechanisms. [ABSTRACT FROM AUTHOR]