Salmonella Typhi can chronically persist within the gallbladder of patients suffering from gallbladder diseases. This study, intended to improve our understanding of bacterial mechanisms underlying bile adaptation, revealed that bile, which is a bactericidal agent, led to the generation of reactive oxygen species in S. Typhi. Salmonella Typhi in response showed a significant increase in the production of anti-oxidative enzymes, namely superoxide dismutase and catalase. The work reports that the quorum-sensing (QS) system of S. Typhi regulates the level of these enzymes during oxidative stress. In support of these observations, the quorum-sensing mutant of S. Typhi was found to be sensitive to bile with significantly lower levels of anti-oxidant enzymes compared to other clinical isolates. Furthermore the addition of exogenous cell-free extracts (CFEs) of S. Typhi containing the quorum-sensing signalling molecule significantly increased the levels of these enzymes within the mutant. Interestingly the CFE addition did not significantly restore the biofilm-forming ability of the mutant strain when compared with the wild-type. In the presence of ciprofloxacin and ampicillin, S. Typhi formed persister cells which increased >3-fold in the presence of bile. Thus the QS-system of S. Typhi aids in oxidative stress management, and enhanced persister cell populations could assist chronic bacterial persistence within the gallbladder.