The homogeneous conversion of cellulose to cellulose propionate with propionic acid anhydride in the ionic liquid 1-ethyl-3-methylimidazolium acetate and two different co-solvents, dimethyl sulfoxide and 1-methylimidazole, was studied. The software MODDE was used to generate an experimental design and evaluate the significance of the studied parameters. The methods 1H and 13C nuclear magnetic resonance (NMR) spectrometry and ion chromatography were used to analyze the obtained materials both qualitatively and quantitatively. The NMR spectrometry of dissolved cellulose esters confirmed there was covalent bonding with an even distribution pattern. From both ion chromatography and NMR spectroscopic data, it was concluded that by adding large amounts of co-solvent and using a high reagent-to-anhydroglucose unit ratio, it was possible to reduce the amount of acetylation caused by acetate anions in the ionic liquid. At the same time, it was shown that the reaction time and temperature was not at all significant in this respect. There was no notable difference detected in the degree of substitution between the reactions performed using dimethyl sulfoxide or 1-methylimidazole as a co-solvent.