Background & objectives: The emergence of multidrug-resistant Salmonella over the last two decades poses a major health risk. In this context, antimicrobial peptides have found a strategic place in the therapeutic armamentarium. Previously, we found that cryptdin-2 has the potential to augment the activity of conventional second- and third-generation anti-Salmonella antibiotics as evident by in vitro assays. In continuation to this, the present study was designed to evaluate the in vivo synergistic effects, if any, of cryptdin-2 in combination with ciprofloxacin and ceftriaxone against murine salmonellosis. Methods: Scanning electron microscopy (SEM) studies along with in vivo synergistic studies were performed using cryptdin- 2 and antibiotic combinations. In addition, peroxidative liver damage, levels of nitric oxide (NO) and antioxidant enzymes along with tumour necrosis factor-alpha (TNF-α) levels were also measured. Results: The SEM results revealed marked changes on the outer membrane of the bacterial cells treated with various combinations. Both the tested combinations demonstrated synergistic in vivo potency against S. Typhimurium as evident by reduction in the number of Salmonellae in the liver, spleen and intestine. Analysis of peroxidative liver damage, levels of NO and antioxidant enzymes along with TNF-α and nuclear factor-kappa B levels revealed that the tested combinations restored their levels to near normal. The most potent combination was found to be that of cryptdin-2 and ciprofloxacin in terms of direct killing and immunomodulatory potential. Interpretation & conclusions: These findings suggest that cryptdin-2 may act in conjunction with conventional antibiotics indicating the possibility of developing these combinations as additional therapeutic agents to combat Salmonella infections.