Mango (Mangifera indica Linn.) trees have been cultivated and grown in Southern and Eastern India for thousands of years and have slowly spread all over the world. For over 4,000 years various parts of mango trees including leaf and fruit pulp have been extensively used in Ayurvedic and Unani medicines. Mango pulp and leaves contain diverse health promoting chemical constituents including mangiferin, a natural polyphenol of C-glycosylxanthone structure, with diverse pharmacological/physiological activities including the promotion of gut health and regularity, as well as antioxidant and anti-inflammatory benefits. This review provides a detailed discussion of the nutritional benefits of mango leaf extract and mangiferin in promoting anti-inflammatory, antioxidant, gastrointestinal and gut health benefits. In addition, information regarding the tissue protective, immunomodulatory, antidiabetic, anti-hyperlipidemic and anti-cancer properties, as well as for disease management and health benefits of mango leaf extracts and mangiferin will be reviewed. Furthermore, mechanistic studies involving the free radical scavenging ability of mangiferin as well as its ability to exert antiinflammatory activity by inhibiting the expression of the TNF-α and related signaling mechanisms and inducible nitric oxide synthase will be considered.