Flurbiprofen (FB) is an effective nonsteroidal anti-inflammatory and BCS class II drug and its poor solubility plays a critical role in limiting its bioavailability. Nanosuspensions can be defined as nanosized colloidal dispersions of drug particles stabilized with stabilizers. The solubility of poor soluble drugs can be increased thanks to their small size and large surface area. The aim of this study is to optimize FB nanosuspensions. The formulations were stabilized with Plantacare 2000(?) as a surfactant using a combination of High Speed Homogenization (HSH) and High Pressure Homogenization techniques (HPH). We also investigated the effects of the critical process parameters (CPPs) of these techniques (homogenization speed & time for HSH and homogenization pressure & cycle for HPH) on three critical quality attributes of nanosuspensions, being the particle size (PS), polydispersity index (PDI) and zeta potential (ZP). After the optimization of HSH, the macrosuspension was transferred to a high pressure homogenizer. After producing FB nanosuspensions by the HPH technique, seven processes which comprise different homogenization pressures, or combinations and different cycles, were applied. Due to the combination of HSH and HPH techniques and the optimization of CPPs, an optimum formulation for a dermal application was found using a 3(3) full factorial design with these process parameters, and characterization studies were also performed.