The crucial challenge associated with water-based drilling fluids for the extraction of shale gas is the inhibition of clay hydration in the drilling operation. The inhibition efficiency of shale inhibitors is determined by the content of particular groups in the molecule. In this report we studied the inhibition performance, inhibition mechanism, and environmental friendliness of three inhibitors containing different amine and hydroxyl groups. It is known that amine groups can replace cations in the molecular chain, decrease basal spacing, exhibit superior inhibition performance, and have better biodegradability. However, hydroxyl groups are less toxic. Thus, the inhibitor molecule should contain both amine and hydroxyl groups, where amine groups detarmine inhibition capacity, and hydroxyl groups provide excellent biotoxicity.