5-Hydroxymethylfurfural (5-HMF) is an important chemical generated from lignocellulosic biomass (LCB) to produce a wide variety of value-added chemicals, biofuels, and biochemicals. Different forms of ionic liquids (ILs) have been utilized for the formation of 5-HMF from LCB. However, 5-HMF is highly soluble in imidazolium-based ionic liquids (IMILs), which makes it difficult to separate after its formation from LCB. In this manuscript, we perform all-atom molecular dynamics simulations to investigate the performance of several aprotic solvents in the extraction of 5-HMF from various IMILs. We consider twelve aprotic solvents with different physicochemical properties, such as acetonitrile (AN), acetone (AT), 1,4-dioxane (DI), N,N-dimethyl acetamide (DMA), N,N-dimethyl formamide (DMF), dimethyl sulfoxide (DMSO), gamma-butyrolactone (GBL), gamma-valerolactone (GVL), hexamethylphosphoramide (HMPA), N-methyl pyrrolidone (NMP), propylene carbonate (PC), and sulfolane (SF). We analyze various structures and dynamics and perform a detailed thermodynamic analysis to understand the underlying molecular behavior. The results indicate that solvents AT and DI showed the least favorable interactions with 5-HMF, whereas HMPA showed the most favorable interactions with 5-HMF. Based on the detailed structural insights, HMPA enhances the separation of 5-HMF from the ILs. Furthermore, different anion combinations were tested to benchmark their separation capability. Overall, the results presented in this manuscript guide the selection of solvent and IL combinations for the effective separation of 5-HMF.