The aim of this work is to investigate the solubility enhancement of mefenamic acid (MA), a non-steroidal anti-inflammatory agent, by formation of stable amorphous ternary system (MA, polyvinylpyrrolidone (PVP), β-cyclodextrin (β-CD)) compared to the binary system (MA, β-CD). Firstly, on the basis of the molecular docking simulation and job’s plot results, three methods were adopted for the preparation of the binary inclusion complexes at the ratio of 2:1 of MA:β-CD, namely solvent co-evaporation (CE), kneading (KN) and physical mixture (PM). However, in order to decrease tendency to self-assembly of cyclodextrins and form aggregates in aqueous media, each binary system was co-milled at ambient temperature in presence of different ratios of a highly water-soluble polymer (PVP). These complexes were characterized using Fourier-transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), X-ray powder diffraction (XRPD), nuclear magnetic resonance (¹H- and ¹³C-NMR) spectroscopy and scanning electron microscopy (SEM) techniques. The release of the drug from the diverse formulations was also investigated by means of UV-VIS spectroscopy. Finally anti-inflammatory and anti-nociceptive activities were performed. The results showed that the solubility of MA in water from ternary complexes was significantly improved.