Objective: Staphylococcus aureus (S. aureus) is a potent causative organism of septic arthritis. In this study, ciprofloxacin was used to nullify the bacterial burden in mice infected with pathogenic strain of S. aureus. Since, endogenous nitric oxide (NO) and prostaglandins (PG) are involved in several inflammatory diseases, in vivo modulation of their levels via Aminoguanidine (AMG) and Meclofenamic acid (MFA), in combination with ciprofloxacin, are used to modulate the inflammatory conditions in bacterial arthritis. Methods: Septic arthritis were induced in mice by S. aureus (i. v.) infection followed by AMG or MFA treatment with ciprofloxacin. Mice were sacrificed at 3, 9 and 15 days post-infection (DPI). The clinical signs of septic arthritis were recorded, bacterial density determination in blood, spleen and synovial tissue, several biochemical, enzyme assays and histological studies of the synovial joint was performed. Results: AMG or MFA treatment alone does not lead to bacterial clearance since endogenous NO or PG was limited for bacterial killing. Ciprofloxacin treatment in combination with either AMG or MFA showed mitigation of bacterial burden as is evident from the CFU count and maximum reduction in inflammatory conditions, apparent from the reduced percentage of induction of septic arthritis, decreased myeloperoxidase (MPO), lysozyme activities, level of serum uric acid and creatinine as well as from the histological examinations. Conclusion: The combination treatment of ciprofloxacin along with immune modulators, AMG or MFA may lead to diminution of the inflammatory build up caused by S. aureus induced septic arthritis in mice. © 2015, International Journal of Pharmacy and Pharmaceutical Sciences. All Rights Reserved.