Mimusops zeyheri Sond. (Milkwood) is an indigenous fruit tree species with considerable ecological, cultural, and nutritional significance that remains underexploited. This review synthesizes current knowledge on its distribution, taxonomy, phytochemistry, ethnomedicinal applications, ecological functions, genetic diversity, and biotechnological potential. A systematic literature search, spanning 1949 to April 2024, yielded 87 relevant publications from an initial 155. Mimusops zeyheri plays a crucial role in supporting the cultural traditions and economic activities of Indigenous Southern African Communities. Its distribution encompasses South, East, and Southern Tropical Africa, with substantial populations across South African provinces. Ethnomedicinally, various plant parts treat conditions including wounds, gastrointestinal issues, and diabetes. The leaves (34%) and roots (32%) are used, with infusion (33%) and decoction (31%) as primary preparation methods. Oral administration (70%) is the most common, primarily addressing skin conditions (18%). Despite its nutritional richness, a standardized nutrient profile is lacking. Limited genetic diversity studies underscore the need for further research. This study highlights Mimusops zeyheri’s multifaceted importance and research gaps, particularly in other Southern African countries. Future investigations should focus on comprehensive phytochemical analysis, ethnomedicinal validation, ecological conservation, genetic diversity assessment, and biotechnological applications. Multidisciplinary collaborations are recommended to promote sustainable utilization while preserving traditional practices.