A systematic strategy for the screening of organic solvents and ionic liquids as entrainers along with the design of the corresponding homogeneous extractive distillation processes has been developed. The proposed approach is illustrated by an example of the entrainer screening in the dehydration of tert-butanol. The toxicity and the physical properties of two types of entrainers (e.g., 19 organic solvents and 289 ionic liquids) are first considered. Then, the properties related to separation performance are further evaluated and three organic solvents and 11 ionic liquids are found to conform to the process feasible restrictions. In the third step, glycerol, tiethylene glycol, 1-butyl-3-methylimidazolium thiocyanide [C4MIM] [SCN), and 1-pentyl-3-methylimidazolium thiocyanide [C5MIM][SCN] are chosen as the representatives to perform thermodynamic topological analysis. Finally, the process design and optimization with four entrainers are performed using the minimization of total annualized cost as the objective function. And the process economic evaluation proves that the ability of glycerol in separating tert-butanol-water system is superior to those of 18 organic solvents candidates while that of [C4MIM] [SCN] is the most advantageous entrainer among 289 ILs in terms of saving energy.