Four kinds of acidic ionic liquids (ILs) were synthesized to hydrolyze keratin with microwave radiation for the first time, among which 1-propylsulfonic-3-methylimidazolium hydrogensulfate ([PSmim]HSO4) presented the best performance for the sample of wool. Then the effects of ionic liquid concentration, solid–liquid ratio, duration, and microwave power on the hydrolysis rate of wool were investigated. After that, the optimum hydrolysis conditions for keratin were determined as: 2 mol/L [PSmim]HSO4, radiation time of 3 h, solid–liquid ratio of wool to ionic liquid at 1:10, microwave power of 300 W, and the final hydrolysis rate of wool was more than 98%; besides that, the swelling effect and kinetics of related processes were also explored, and the hydrolysates were characterized by infrared spectra (IR) and thermalgravimetric analysis (TGA), which were further compared with the product hydrolyzed by traditional volatile strong acid. Furthermore, this IL-catalyzed microwave-assisted method was also applied to hydrolyze a series of feathers and hairs with the comprehensive comparison on the antioxidant activity, free amino acid concentration, and molecular distribution of hydrolysates. The recovered ionic liquid by resin was not changed from its original status obviously, which could be reused and improve the economy of the whole process. Compared with conventional ways, higher hydrolysis degree can be obtained by the developed method, which was a high-efficient, low consumption and environmentally friendly technique.