Metal oxides, especially magnesium oxide (MgO), are the most commercialized and eco-friendly nanomaterials (NMs) and possess enormous applications in diversified medical and environment sectors, including sound-absorbing panels and sensors, therapeutics, antipathogenic strategies, and renewable energy harvesting. However, the manufacturing and processing metal oxide NMs require sustainable routes in terms of eco-friendly operation, cost-effectiveness, and utilization of renewable precursors. Green synthesis is poised to be the route to sustainability in the NM synthesis sector since it is an environmentally friendly technique that produces no toxic waste and employs less hazardous chemicals and solvents. It involves the utilization of various biomes and biowaste, including plant extract, essential oil, microbes, agricultural waste, and human waste. This chapter discusses the state-of-the-art green approach to synthesizing MgO nanoparticles using neem (Azadirachta Indica) leaf extract. As a medicinal plant, neem has a wide range of biomedical benefits and is rich in phytochemicals (flavonoids, polyphenols, nimbin, salannin, quercetin, etc.), which can mediate to fabricate NMs. Moreover, it is easily accessible, renewable, and naturally eco-friendly. This chapter delves into the phytochemical analysis of neem leaf extracts and their role in NM synthesis, their utilization to produce biogenic MgO nanoparticles, and their applications in diversified sectors, especially in the fields of one health, particularly antibacterial, antimicrobial, antioxidant, and anti-cancer effects. This chapter, while providing the in-depth fundamental background for advancements in the field of green synthesis towards the efficient preparation of NPs, such as MgO, for implementation in future applications, also discusses the challenges, their alternate solutions and prospects of green nanotechnology as the road to sustainability in NM fabrication.