Bioisoprene, which can be produced from renewable feedstocks through fermentation, is a promising alternative to petroleum-derived isoprene. However, challenges including the selection of feasible recovery techniques for bioisoprene should be addressed to achieve economic and technical competitiveness. In this work, ionic liquids (ILs) are first introduced as solvents for the recovery of bioisoprene. To describe the thermodynamic behavior, the UNIFAC-IL model is first extended to the bioisoprene systems as it combines gas–organic chemicals in IL-containing systems. Using a computer-aided IL design (CAILD) method, six out of 248 742 structurally constrained ILs are screened as optimal candidates for their further performance evaluation. Simulation results indicate that all six ILs have much better process performance than that of the alternative, isopropyl myrisate. Moreover, [N1,1,3,0][DMP] is identified as the best IL with the lowest solvent flow rate and the highest recovery ratio of isoprene. This work shows the potential of using ILs for the recovery of bioisoprene from fermentation off-gas.