A high-performance Ni/ZnO-Al2O3-SiO2 adsorbent was developed for reactive adsorption desulfurization (RADS) of diesel. The desulfurization performance of the prepared adsorbents was evaluated in a fixed-bed reactor for treating a hydrotreated diesel with a sulfur content of 1187 ppm. The preparation conditions were investigated, such as aging time, aging temperature, metallic ion concentration, and precipitation temperature. Results showed that the adsorbents performed at a high desulfurization efficiency under the mild preparation conditions. This indicated that smaller crystalline grains were favorable for desulfurization over the Ni/ZnO-Al2O3-SiO2 adsorbent. The adsorbent attained a high adsorption ability of 38.4 mg/g at a breakthrough sulfur level of 20 ppm. The mechanism of deactivation of the adsorbent was also studied and discussed by various characterizations, such as N-2 physisorption, powder X-ray diffraction (XRD), ammonia temperature-programmed desorption (NH3-TPD), transmission electron microscopy (TEM), and scanning electron microscopy/energy-dispersive spectrometry (SEM/EDS). The main reasons of the deactivation of the RADS adsorbent include the carbon deposition, the formation of ZnS, and the sintering of the active and support.