Hypervirulent Klebsiella pneumoniae (hvKp), one of the most significant pathogens in nosocomial infections, regulates the shift from long-term survival to pathogenicity via an intricate regulatory network. Nevertheless, the mechanism by which hvKp manages to uphold a variety of metabolic shifts occurring in its immediate vicinity could play a significant role in bolstering its virulence. Through the identification of DppA, a crucial component of the dipeptide (Dpp) transporter system, our findings revealed a link between DppA and the regulation of virulence and metabolism in hvKp. Significant phenotypic alterations were observed in the dppA deletion mutant, including increased biofilm formation, improved serum resistance, enhanced siderophores production, improved cell adhesion and infection, and, most crucially, in a mouse model of bloodstream infection, we demonstrated that the dppA deletion markedly increased the expression of the inflammatory mediator IL-6. Furthermore, approximately 2.5 % of the genes exhibited differential expression in the mutant, with virulence-associated genes (particularly those related to siderophores) showing substantially elevated expression levels. This study deciphers the role of DppA within the virulence and metabolic regulatory networks of hvKp, thereby establishing a foundation for future research into its pathogenic mechanisms.