Objective: Tolfenamic acid (TA) is a non-steroidal anti-inflammatory drug that is commonly used in veterinary medicine. However, information on its pharmacokinetics in calves, particularly following subcutaneous (SC) administration, is limited. The aim of this study was to characterize the disposition of TA in calves following SC, intramuscular (IM) and intravenous (IV) administration. Methods: Six calves received TA at a dose of 4 mg/kg via each route in a crossover design. Results: TA exhibited route-dependent pharmacokinetics. The terminal elimination half-life increased significantly from IV (6.64 h) to IM (12.79 h) and SC (15.11 h) administration, which is consistent with flip-flop kinetics following extravascular dosing. Following IV administration, the volume of distribution at steady state was moderate (0.67 L/kg), which suggests extensive plasma protein binding. The time to reach the maximum concentration was similar for the IM and SC routes. However, systemic exposure was markedly lower following SC administration, with peak plasma concentration, area under the curve and bioavailability being approximately half of those observed following IM injection. Plasma concentrations exceeded the EC50 values required to inhibit prostaglandin E2 and related inflammatory mediators for up to 24 h after IV administration and up to 48 h after IM or SC administration. Conclusions: These findings demonstrate that SC administration of TA in calves results in prolonged but reduced systemic exposure compared with IM administration. The results support the need for route-specific dosing considerations and provide a basis for further studies on residue depletion and determination of withdrawal period in food-producing calves.