Salmonella infections represent a major health hazard and have been responsible for a number of epidemics. In view of the emergence of multidrug-resistant Salmonella strains, there is a need for therapeutic alternatives. The purpose of this study was to evaluate the therapeutic potential of cryptdin-2 (a Paneth cell antimicrobial peptide) against Salmonella infection. The bactericidal activity of cryptdin-2 against Salmonella enterica serovar Typhimurium NCTC74 was evaluated in vitro, ex vivo and in vivo on the basis of cfu enumeration. The MBC of cryptdin-2 for Salmonella Typhimurium was found to be 19 mg/L. The ex vivo study demonstrated significantly higher intracellular killing of the bacteria by macrophages treated with cryptdin-2 as compared with untreated macrophages. Treatment of infected mice with cryptdin-2 resulted in significant clearance of Salmonella from livers, spleens and intestines. The therapeutic efficacy of cryptdin-2 suggests that it may be a promising option to combat Salmonella infections or at least may act as an adjunct to conventional antibiotics.