The objective of this study was to determine the effect of ketoprofen (3 mg/kg, IV) on the pharmacokinetics of marbofloxacin administered intravenously at 2 and 10 mg/kg in sheep, and to identify possible changes in key pharmacokinetic parameters when combined. Twelve healthy Merino sheep were enrolled in a two-stage crossover pharmacokinetic study. Each animal received intravenous marbofloxacin at 2 and 10 mg/kg, administered either alone or in combination with ketoprofen (3 mg/kg, IV). Blood samples were collected over 48 h, and plasma marbofloxacin levels were measured using HPLC-UV. Pharmacokinetic parameters were calculated by non-compartmental analysis. Compared to the 2 mg/kg dose, the AUC and t1/2ʎz increased and ClT decreased at the 10 mg/kg dose of marbofloxacin (p < 0.05). Combination administration with ketoprofen decreased ClT and Vdss values in both dose groups, and increased AUC and t1/2ʎz values (p < 0.05). Ketoprofen significantly alters marbofloxacin's pharmacokinetic parameters, increasing its systemic exposure. It is thought that the increased AUC, especially with high-dose or combined administration, may enhance antibacterial efficacy by raising the AUC/MIC ratio. Potential drug interactions should be considered in clinical practice.