Avanafil (AVA) is a second-generation phosphodiesterase-5 (PDE5) inhibitor. AVA shows high selectivity to penile tissues and fast absorption, but has a bioavailability of about 36%. The aim was to formulate and optimize AVA-biodegradable nanoparticles (NPs) to enhance AVA bioavailability. To assess the impact of variables, the Box-Behnken design was utilized to investigate and optimize the formulation process variables: the AVA:poly (lactic-co-glycolic acid) (PLGA) ratio (/, X1); sonication time (min, X2); and polyvinyl alcohol (PVA) concentration (%, X3). Particle size (nm, Y1) and EE% (%, Y2) were the responses. The optimized NPs were characterized for surface morphology and permeation. Furthermore, a single-oral dose (50 mg AVA) pharmacokinetic investigation on healthy volunteers was carried out. Statistical analysis revealed that all the investigated factors exhibited a significant effect on the particle size. Furthermore, the entrapment efficiency (Y2) was significantly affected by both the AVA:PLGA ratio (X1) and PVA concentration (X3). Pharmacokinetic data showed a significant increase in the area under the curve (1.68 folds) and plasma maximum concentration (1.3-fold) for the AVA NPs when compared with raw AVA. The optimization and formulation of AVA as biodegradable NPs prepared using solvent evaporation (SE) proves a successful way to enhance AVA bioavailability.