Etoricoxib is an anti-inflammatory drug largely used in a variety of acute and chronic inflammatory diseases, but is associated with low aqueous solubility and poor dissolution leading to a delayed rate of absorption and onset of action. This study focuses on the development and pharmacological evaluation of a series of binary systems of etoricoxib with cyclodextrins. The binary systems of etoricoxib with beta-cyclodextrin (beta-CD) and 2-hydroxypropyl-beta-cyclodextrin (HP-beta-CD) were prepared by the kneading method. Drug-cyclodextrin interactions in solution were investigated by the phase solubility analysis. X-ray diffractometry studies were carried out for the characterization of all binary systems. In vivo studies were performed using the tail flick and Eddy's hot plate apparatus. The results of the phase solubility studies indicated an increase in etoricoxib solubility upon complexation with beta-cyclodextrin (stability constant, Kc value of 198.6 and 209.9 L/mol for 1:1 and 1:2 beta-CD complexes of the drug, respectively) and a further increase on complexation with HP-beta-CD (stability constant, Kc value of 265.3 and 355.8 L/mol for 1:1 and 1:2 HP-beta-CD complexes of the drug, respectively). Results of the in vivo drug activity studies also pointed towards an enhanced antinociceptive effect of etoricoxib upon cyclodextrin complexation with 1:2 drug HP-beta-CD complex showing maximum effect.