Research in recent years has revealed a dynamic interplay between metabolism and immune responses in health and disease. The potential of metabolic hormones regulating innate immunity against infections have been less understood. Here, we studied the crosstalk between leptin signaling and macrophage functions in the context of bacterial infections. We found that upon infection with Gram-negative pathogens such as Salmonella Typhimurium, macrophages increased their leptin receptor (Lepr) expression. Genetic ablation of Lepr in macrophages or antagonizing leptin pharmacologically led to augmented lysosomal functions, reduced S. Typhimurium burden and reduced inflammation in vitro and in vivo. Mechanistically, leptin induction leads to activation of the mTORC2/Akt pathway and downregulation of Phlpp1 phosphatase, which dephosphorylates Akt, thereby impairing lysosomal function and pathogen clearance. Our results highlight a novel link between leptin signalling, mTORC2/Phlpp1/Akt axis and lysosomal activity of macrophages with important therapeutic implications for modulating innate immunity in combating Gram-negative bacterial pathogens.