This study examines the effects of different doses of dexamethasone on the behavior of danofloxacin in the plasma and milk of lactating sheep. Understanding this interaction is crucial as both drugs are frequently used in veterinary medicine and may influence therapeutic effectiveness and milk safety. The research involved six lactating ewes, with plasma and milk samples collected at various intervals after administering low and high doses of dexamethasone alongside danofloxacin. The results revealed that although dexamethasone did not alter danofloxacin disposition in the plasma, it significantly increased its concentration in the milk, particularly at higher doses. This raises important concerns for both therapeutic efficacy and milk safety, as it indicates that milk from sheep treated with dexamethasone could contain higher danofloxacin concentrations. Overall, the findings underscore the need for careful evaluation of these medications’ combined use to ensure both optimal treatment outcomes for animals and the safety of milk products for consumers.