Atomistic level understanding of the interactions of thiophene and iso-octane with various organic solvents such as N-methylpyrrolidone (NMP), sulfolane, furfural, diethyleneglycol (DEG), 2-aminoethanol (ETA), tetraethyleneglycol (TEG), dimethylformamide (DMF) and cyrene to find an optimum solvent for selective extraction of thiophene, was presented by using DFT and MD simulations. As per the reactivity descriptors computed from Koopmans’ theorem based on quantum mechanics, for the eight solvents studied, furfural is most reactive followed by cyrene while sulfolane has the least reactivity. Based on the interaction energies (IE) of solute–solvent systems using DFT, cyrene presented strongest interaction with thiophene followed by TEG, furfural and DEG indicating that cyrene can show good thiophene removal capacity. The difference in the IE values of thiophene and isooctance was considered as a measure of possible sulphur selectivity over hydrocarbon. Among the eight solvents considered, furfural, DEG, TEG and cyrene observed to show good desulfurization selectivity. The favourable positions on solvent molecules for potential interactions with thiophene and isooctane were identified using orbitals, electrostatic potential maps, fukui function maps for electrophilic and nucleophilic attack, match well with the trends in IE values and RDFs from MD simulation. The solute–solvent concentration profiles and radial distribution functions computed using MD simulations evidently show that furfural and cyrene show better capacity and selectivity for Thiophene which are in correspondence with DFT results. The detailed analysis using QM and MM methods, concludes that cyrene, furfural and TEG are the optimum organic solvents for thiophene removal from gasoline using extractive desulfurization method (EDS). © 2022, The Author(s), under exclusive license to Springer Nature Switzerland AG.