Over the past few years, the interest of material scientists for metal and metal oxide nanoparticles (NPs) is increasing dramatically because of their unique physicochemical characteristics such as catalytic activity and optical, electronic, antibacterial, and magnetic properties which depend on their size, shape, and chemical surroundings. Recently, several new routes of synthesis of lead monoxide (PbO) nanoparticles have been used, such as chemical synthesis, calcination, sol-gel pyrolysis, anodic oxidation, solvothermal method, thermal decomposition, chemical deposition, laser ablation, and green methods. Essentially, for the structural characterization of lead oxide nanoparticles, several spectroscopic, microscopic, and thermogravimetric methods of analysis are used. Lead oxide has been widely utilized in batteries, gas sensors, pigments, ceramics, and glass industry. Furthermore, lead oxide nanoparticles are graded as toxic and dangerous for the human health and environment. Therefore, there is an urgent need to develop new approaches and standardized test procedures to study the potential hazardous effect of nanoparticles on the human health and environment. The aim of this chapter is to provide an overview of the recent trends in synthesis of lead oxide nanoparticles, their characterization, possible applications, and toxicity.