To cope with the increasingly severe challenges of zinc oxide nanoparticles (ZnO-NPs) in the field of the aquatic environment, this paper uses poly-aluminum ferric chloride (PAFC) and cationic polyacrylamide (CPAM) as coagulants to enhance the removal of ZnO-NPs from water. In two environments (pure-water environment and kaolin environment) that simulate suspended solids, we studied the dosage, pH, precipitation time, and hydraulic power of ZnO-NPs at three different initial concentrations (1, 2, and 30 mg/L). The effects of various conditions on the performance of PAFC, CPAM, and PAFC/CPAM to remove ZnO-NPs were examined. Results showed that the overall removal rate of ZnO-NPs in the kaolin environment was slightly higher than that in the pure-water environment. In contrast the removal rate of ZnO-NPs in the PAFC/CPAM was significantly higher than that of PAFC or CPAM alone. The coagulation removal conditions of ZnO-NPs were optimized using a response-surface model. Under the best conditions, the removal rate of ZnO-NPs with an initial mass concentration of 30 mg/L in the PAFC/CPAM combination in pure-water and kaolin environments was 98.54% and 99.17%, respectively. Finally, by studying the changes in floc size during coagulation, enhanced coagulation was an efficient method of removing ZnO-NPs from water.