Microparticles charged by niflumic acid and based on cellulose derivatives as polymeric matrices, that is, ethylcellulose (EC) and mixtures of EC and hydroxypropylmethylcellulose (HPMC), were elaborated using microencapsulation by emulsion-solvent evaporation technique. The niflumic acid is considered as a poorly water soluble drug, so the main objective of the paper is to use designs of experiment in order to prepare new solid formulations with a large range of size for the drug dissolution enhancement. The possible drug-polymer interaction was investigated by Fourier transform-infrared spectroscopy, X-ray diffraction, and differential scanning calorimetric analysis. Some of the process variables, namely, the stirring speed of emulsion, the emulsifier concentration, and the EC:HPMC ratio, were selected and varied. Their main and interactive effects on the microparticles' characteristics were obviously evaluated and discussed using Minitab software 16.1. The obtained microparticles' size (d 10 ) ranged from 196 to 796 μm, and the drug entrapment reached 45% in some formulations. The drug dissolution results showed that the Higuchi's release constant varied from 0.011 to 0.067 min −1/2 and was enhanced especially when the HPMC concentration was increased.