Salmonella Typhi secretes typhoid toxin that activates cellular DNA damage responses (DDR) during acute typhoid fever. Human infection challenge studies revealed that the toxin suppresses bacteraemia via unknown mechanisms. Using quantitative proteomic analysis on the plasma of bacteraemic participants, we demonstrate that wild-type toxigenic Salmonella induced secretion of lysozyme (LYZ) and apolipoprotein C3 (APOC3). Recombinant typhoid toxin or Salmonella infection recapitulated LYZ and APOC3 secretion in cultured cells, which involved ATM/ATR-dependent DDRs and confirmed observations in typhoid fever. LYZ caused spheroplast formation, inhibited the Salmonella type 3 secretion system, and intracellular infections. LYZ expression was regulated by p53 in a cell type-specific manner and driven by mitochondrial oxidative stress that caused nuclear DDRs and p53-mediated senescence responses. Addition of LYZ inhibited oxidative DNA damage and resulting senescence responses caused by typhoid toxin. Our findings may indicate that toxin-induced DDRs elicit antimicrobial responses, which suppress Salmonella bacteraemia during typhoid fever.