Nowadays, there is a need for good and efficacious NSAIDs with minimal side effects to be applied in veterinary medicine. The aim was to compare the pharmacodynamics (analgesia and inhibition of COX-2) and pharmacokinetics between selective (nimesulide) and non-selective (aspirin) COX-2 inhibitors in mice. Assessing the median effective doses by using the up-and-down method, COX-2 activity and plasma concentrations for both nimesulide and aspirin with their pharmacokinetic profiles in mice. The median effective doses (ED50s) of nimesulide and aspirin were found to be 7.9 and 212.23 mg/kg, respectively, using the hot-plate. Both nimesulide (15.8 mg/kg, i.m.) and aspirin (424.5 mg/kg, i.m.) inhibited COX-2 activity through a decrease in COX-2 concentrations in the plasma, liver, and kidney of mice, with superior inhibition when administering nimesulide in comparison to the control (negative and positive) and aspirin-treated groups. Plasma concentrations of nimesulide (15.8 mg/kg, i.m.) measured for different comparable periods of 0.5, 1, 2, 4, and 24 hours were higher than those of aspirin, which were 14.62, 9.22, 9.88, 7.38 and 2.27 µg/ml, respectively, while aspirin (424.5 mg/kg, i.m.) was 4.35, 3.17, 2.54, 2.25 and 1.21 µg/ml, at the same measured times. Nimesulide pharmacokinetic variables were estimated to be AUC0-∞ 169.18, AUMC0-∞ 2358,72, Kel  0.06, Cmax 14.62, Tmax 0.5, t1/2β 11.07, MRT 13.94, Vss 1.49, and Cl 0.09, while aspirin pharmacokinetic parameters differed to be 82.31, 2428.32, 0.03, 4.35, 0.5, 21.25, 158.12, and 5.16, respectively. The study concluded that nimesulide has superior pharmacological properties (analgesic, antipyretic, and anti-inflammatory) than aspirin due to its ability to inhibit COX-2 more selectively and its unique pharmacokinetics in mice, which may be useful in veterinary medicine.