The dissolution of chitosan is a tedious and time-consuming process. Herein, we select the best Ionic Liquids (ILs) for chitosan dissolution through the application of Conductor-like Screening Model for Real Solvents (COSMO-RS), which allowed the screening of 640 ILs based on 32 cations based on amino acids, imidazolium, pyridinium, and pyrrolidinium, and 20 selected anions such as C2H3O2, Cl, NO3, BF4, and others. Thermodynamic properties such as logarithmic activity coefficient at infinite dilution (ln γ) and excess enthalpy (HE) were used to evaluate the dissolution potential of ILs towards chitosan, whereby low values of ln γ and HE indicated better engagement between the solute and the solvent, thus resulting in a higher solute being dissolved. A preliminary screening of chitosan dissolution was carried out in all 5 synthesized ILs to validate the results obtained by COSMO-RS. It was observed that ILs with BF4� as the anion and cations such as Ser, Gly, Phe, Cys, and Asn have the lowest ln γ values, hence better interaction with chitosan. The values of HE indicated that the molecular interactions between chitosan and ILs were governed by hydrogen bonding (ranging from 37 to 50%), followed by misfit interactions (ranging from 21 to 31%) and van der Waals forces (ranging from 22 to 32%) due to the abundance of hydroxyl (-OH) groups present in the intermolecular and intramolecular chitosan structures. These proved the great ability of COSMO-RS to accurately predict the dissolution of chitosan in ILs. © 2024 The Royal Society of Chemistry.