Scutellariae radix (SR) has been proven to be highly effective in treating inflammation because of its superior medicinal properties. The two main commercial specifications of SR are Kuqin (KQ) and Ziqin (ZQ). According to traditional Chinese medicine theories, KQ has a better effect than ZQ on dispelling upper energizer lung damp heat, however, its mechanism of action is not known. Thus, this study investigated the role of KQ-induced alterations in endogenous metabolites and gut microbiota in regulating LPS-induced acute lung injury (ALI). KQ treatment ameliorated lung injury more effectively than ZQ and demonstrated satisfactory organ protection properties. KQ treatment reversed the tryptophan metabolite abnormalities in ALI and reshaped the composition of gut microbial communities. Additionally, the abundance of the enriched Akkermansia muciniphila was significantly and inversely correlated with the rate-limiting enzyme of the tryptophan/kynurenine pathway, indoleamine 2,3-dioxygenase 1 (IDO1) activity (p = 0.0214, R² =0.7712). Furthermore, the beneficial and causative effects of A. muciniphila were confirmed by antibiotic and microbial intervention experiments. Live and pasteurized A. muciniphila, both supplements could ameliorate the inflammatory response and down-regulate IDO1 expression, thereby restoring tryptophan metabolic imbalance. In conclusion, the current study demonstrated for the first time that KQ may act on the A. muciniphila abundance, regulate IDO1 activity, and thus ameliorate ALI. Interestingly, A. muciniphila supplementation could be a promising therapeutic option for lung diseases through the gut-lung axis.