Tuberculosis is a serious public health problem aggravated by the slow progress in the development of new anti-tuberculosis drugs. The hyper-reactive TB patients have suffered from chronic inflammation which could cause deleterious effects on their bodies. Therefore, it is imperative to develop an adjunctive therapy based on inflammatory modulation during Mycobacterium tuberculosis (Mtb) infection. The present study aims to investigate the immune regulatory effects of Andrographolide (Andro) on Mtb-infected macrophages and its underlying mechanisms. The results showed that Andro inhibits the production of IL-1β and other inflammatory cytokines in a dose-dependent manner. The down-regulation of IL-1β expression causes the declining expression of IL-8 and MCP-1 in lung epithelial cells which were co-cultured with Mtb-infected macrophages. The inhibition of the activation of NF-κB pathway, but not the inhibition of MAPK signaling pathway, accounts for the anti-inflammatory role of Andro. Further studies elucidated that Andro could evoke the activation of autophagy to degrade NLRP3, which ultimately inhibited inflammasome activation and subsequent IL-1β production. Finally, the relevant results demonstrated that Andro inhibited the Notch1 pathway to down-regulate the phosphorylation of Akt/mTOR and NF-κB p65 subunit. Taken together, Andro has been found to suppress the Notch1/Akt/NF-κB signaling pathway. Both Akt inhibition-induced autophagy and inhibition of the NF-κB pathway contributed to restraining the activation of NLRP3 inflammasome and subsequent IL-1β production. Then, the decreased production of IL-1β influenced chemokine expression in lung epithelial cells. Based on these results, anti-inflammatory effect of Andro in TB infection is merit further investigation.©2020 Society for Leukocyte Biology.