Pathogenesis of periodontitis is marked by microbiota dysbiosis and disrupted host responses. Porphyromonas gingivalis is a keystone pathogen of periodontitis which expresses various crucial virulence factors. This study aimed to clarify the role and mechanisms of P. gingivalis tryptophan-indole metabolic pathway in the pathogenesis of periodontitis. This study showed that periodontitis patients exhibited elevated tryptophan metabolism and salivary pathogen abundance. Tryptophanase gene-deficiency altered proteome and metabolome of P. gingivalis, inhibited P. gingivalis virulent factors expression, biofilm growth, hemin utilization, cell adhesion/invasion and pro-inflammation ability. Tryptophan-indole pathway of P. gingivalis stimulated periodontitis biofilm formation and induced oral microbiota dysbiosis. In periodontitis mice, this pathway of P. gingivalis aggravated alveolar bone loss and gingival tissue destruction, causing oral and gut microbiota dysbiosis. This study indicates that the tryptophan-indole pathway serves as a significant regulator of P. gingivalis virulence and oral microbiota dysbiosis, which is also associated with gut dysbiosis.