Many active pharmaceutical ingredients (API) are poorly soluble in water and their low oral bioavailability is a major hindrance to their potential use. Megestrol acetate (MGA) is insoluble in water and its oral absorption is limited and considerably affected by food. Nanoemulsions (NEs) can be used as effective oral drug delivery systems where the hydrophobic API is loaded into the oil phase. In this study, MGA-loaded NEs were prepared based on the spontaneous emulsification technique. The effects of different excipients such as ethanol, Tween 80, Lipoid E80, and medium-chain triglyceride (MCT) on the NEs characterization were investigated. The experimental results indicated that optimum MGA-loaded NEs (F20) were nanometer-sized droplets (166.9 +/- 3.0 nm) with negative zeta potential (-12.2 +/- 1.1 mV). The effect of polyvinylpyrrolidone (PVP) on characteristic properties of F20 was also evaluated. On the selected NEs, in vitro dissolution tests and stability studies in various mediums and storage conditions were performed. The encapsulation efficiency of NEs were > 99%. The overall droplet size of F20 and PVP-2 (PVP-coated NEs) remained relatively stable as the pH changed from 1.2 to 6.8. It was determined that F20 and PVP-2 remained stable at 4 degrees C until 12 weeks and had higher cytotoxicity on MCF-7 cells. To conclude, droplet size, surface charge, and stability are important properties for NEs to have sufficient effectiveness. In this study, alternative oral NEs of low-solubility drug MGA were developed considering the above features.