The main purpose of this study was to develop nanosuspensions of ziprasidone hydrochloride monohydrate (ZHM), the BCS Class II antipsychotic agent, to solve its water solubility issues, improve oral bioavailability, and reduce the food effect. Microfluidization method was used to obtain nanosuspensions. Effects of formulation and process parameters on particle size (PS), particle size distribution (PDI), and zeta potential (ZP) values were investigated by Design of Experiment (DoE) approach. The Solubility of ZHM in water was determined. The dissolution studies were performed in various media and also FaSSIF and FeSSIF media in comparison with coarse powder, physical mixture, and commercial product. The nanosuspensions were also characterized by SEM, XRPD, DSC. The optimum PS, PDI and ZP values were found with the nanosuspensions stabilized with PVP and Vitamin E. Round shape particles were observed and thermal properties of ZHM were preserved. The solubility was increased 2.3-fold and 1.84-fold with PVP K30 and Vitamin E TPGS stabilized nanosuspensions compared with ZHM coarse powder, respectively. Nanosuspensions showed > 95% dissolution in FeSSIF medium and 80% in FaSSIF medium. In conclusion, ZHM nanosuspensions which was prepared by microfluidization using DoE can enhance water solubility and dissolution as well as decrease the fed/fasted state variations.