Some Melilotus species have been well acknowledged in worldwide traditional medicine, where its folk uses not only heal simple ailments but also used in vital disorders. The current review considers the comparative phytochemical and biological prospective survey of Melilotus messanensis (L.) All. and a medicinal Melilotus species; Melilotus indicus (L.) All., aiming to highlight the medicinal significance for the former species. A chemical survey of both species revealed around 135 metabolites (phenolic acids, coumarins, flavonoids, terpenoids, two saponins, fatty acid esters, and others). Also, their bioactivity studies have been directed to potential antioxidant, antidiabetic, and/or antimutagenic activities, while the folk medicinal properties, as well as the anti-microbial and anti-inflammatory assays were limited to M. indicus. Thus, this review draws attention to further biological research for M. messanensis to discover its medicinal uses. From the chemosystematics point of view, the fruit morphology and the structural chemical variations confirmed the significance of the two species. As well as their chemical resemblances with a well-known commercial medicinal species; Melilotus officinalis (L.) Pall., which predict the significance medicinal outcomes of M. messanensis.