The purpose of the research was to investigate the changes in physicochemical properties and their influence on nasal formulation performance using 5-factor, 3-level Box-Behnken experimental design on the combined responses of viscosity, droplet size distribution (DSD), and drug release. Gel formulations of hydroxyurea (HU) with surface-active polymers (hydroxyethylcellulose [HEC] and polyethylene-oxide [PEO]) and ionic excipients (sodium chloride and calcium chloride) were prepared using Box-Behnken experimental design. The rheology and dynamic surface tension (DST) of the test formulations was investigated using LV-DV-III Brookfield rheometer and T60 SITA tensiometer, respectively. Droplet size analysis of nasal aerosols was determined by laser diffraction using the Malvern Spraytec with the InnovaSystems actuator. In vitro drug release studies were conducted on Franz diffusion cells. With PEO gel, calcium chloride increased the viscosity and DSD and retarded drug release, while sodium chloride decreased the viscosity, DST, and DSD and accelerated the release of HU. With HEC gel, the addition of the above salts resulted in less significant changes in viscosity, DSD, and DST, but both salts significantly increased the release of HU. Droplet size data obtained from a high viscosity nasal pump was dependent on type of polymer, polymer-excipient interactions, and solvent properties. The applications of Box-Behnken experimental design facilitated the prediction and identified major excipient influences on viscosity, DSD, and in vitro drug release.