Microcrystalline cellulose was subjected to acetylation by different agents in solvent mixtures, composed of the ionic liquids (ILs) 1-butyl-3-methylimidazolium X (X = acetate, BuMeImAcO; chloride, BuMeImCl), and the molecular solvents (MSs), N,N-dimethylacetamide (DMAc) and dimethyl sulfoxide (DMSO). The reactions were carried out under homogeneous conditions using the following acetylation agents: acetic anhydride ((Ac)2O), 1-acetyl-3-methylimidazolium acetate (AcMeImAcO), and vinyl acetate (VA). The efficiency of acetylation was judged by the degree of biopolymer substitution, DS. For all binary solvent mixtures, the order of DS was: AcMeImAcO > (Ac)2O > VA. For the same acetylating agent, the order of DS was: BuMeImAcO-DMSO > BuMeImAcO-DMAc > BuMeImCl-DMSO. We rationalize this dependence of DS on reaction conditions by considering our experimental data and the results of molecular dynamics simulations (MD). Thus, solvent-induced separation of cellulose chains leads to higher acetylation rates, hence larger DS values. The order of biopolymer dissolution/chain separation is attributed to a combination of hydrogen-bonding of the IL anion with cellulose hydroxyl groups, and biopolymer-solvent hydrophobic interactions. The results of MD simulations showed an additional important point: the compositions of the cellulose solvation layers are different from those of bulk solvent mixtures; they are richer in IL ions; this difference affects the values of DS. Thus, theoretical calculations help in choosing the best solvents for cellulose dissolution/derivatization.