Gefitinib (GB), an oral tyrosine kinase inhibitor suffers major setbacks in clinical application due to limited aqueous solubility leading to poor oral bioavailability. Nanosuspension serves as a promising formulation strategy to overcome the above-mentioned drawbacks. Hence, the present study involves the development of gefitinib nanosuspension (GB-NS) using High-pressure homogenization (HPH) to increase its aqueous solubility and maximize oral bioavailability. GB-NS was optimized by utilizing the quality-by-design strategy to optimize independent variables such as homogenization pressure, drug-to-stabilizer ratio, and number of cycles. Lecithin was found to stabilize the nanosuspension with optimal particle size, PDI, and zeta potential of 157 ± 18.77 nm, 0.296 ± 0.040, and -33.25 respectively. Intriguingly, a drug-to-stabilizer ratio significantly influenced (p <
0.005) particle size and PDI, establishing its crucial role in optimization. The morphological characterization by SEM of GB-NS revealed a rod-shaped structure. Thereafter, the thermal and powder X-ray analysis depicted the crystalline nature of gefitinib in GB-NS. Additionally, GB-NS exhibited enhanced saturation solubility (~ 2.4- and ~ 3.4-fold) and dissolution rate (~ 2.5- and ~ 3.5-fold) compared to pure GB in 0.1 N HCl and PBS 6.8 respectively. GB-NS remained stable under both storage conditions ( 25°C and 4°C). Finally, the pharmacokinetic study depicted a considerable increase in C