By means of rotational rheometer, microcalorimeter, environmental scanning electron microscope (ESEM) and X-ray diffractometer (XRD), the effects and mechanism of three kinds of water reducer including naphthalene formaldehyde sulfonates (NFS), sulfonated melamine formaldehyde (SMF) and polycarboxylate (PC) on the rheological and setting properties of high-strength gypsum paste (HSGP) were studied systematically. The results show that the order of improving the fluidity of HSGP by the three water reducers is PC>SMF>NFS. The deflocculation effect of water reducer promotes the dissolution of hemihydrate gypsum, delays the nucleation of dihydrate gypsum, and causes the HSGP to produce segregation and shear-thickening. Under the saturated content, NFS delays the nucleation of dihydrate gypsum, but promotes the growth and formation of crystal-network-structure (CNS) of dihydrate gypsum, so it has little effect on the early hydration and setting time of HSGP. SMF promotes both the growth and formation of CNS of dihydrate gypsum crystals, without affecting the nucleation of dihydrate gypsum, thus accelerating the early hydration process of HSGP and shortening the setting time significantly. PC hinders both the nucleation and growth of dihydrate gypsum crystals, thus greatly postponing the early hydration process of HSGP and linearly improving the setting time.