Human populations in various regions across the world exploit the medicinal properties of plants to treat a wide variety of diseases. Areas with both high rates of endemic taxa and persisting traditional uses of the local botanical resources are key sites for the investigation of Traditional Botanical Knowledge (TBK). Commonly, in these areas, information regarding the medicinal properties of native plants has been transmitted orally from generation to generation, however, a rapid decline in this knowledge has been observed, which can be attributed to socio-economic changes in recent years. The Mediterranean basin is one such site, where human history is intimately entwined with nature. The unique geographical situation and unrivaled environmental heterogeneity of the area, have allowed both the development of diverse civilizations as well as providing the basis for the evolution of extraordinary biodiversity. The Mediterranean basin can therefore be considered a global hotspot of endemic vascular plants, and of traditional knowledge of medicinal and aromatic species. This study researches the historical subregion of Marmilla (central-southern Sardinia, Italy), which was chosen because of its specific cultural and demographic characteristics: i.e., prolonged isolation and extreme longevity of the inhabitants of the area. Semi-structured interviews were conducted with 145 people from the region, and 137 medicinal plants belonging to 62 families were identified, of which around 57,3% were taxa exclusive to the Mediterranean Basin. Findings showed that the most used parts of the plant were the leaves (49%), while as far as preparations are concerned, decoction (50%) was the most used to prepare medicinal formulations, making this the highest number of medico-botanical taxa reported in a study carried out in Sardinia using a similar methodology. In addition, this study contributes towards preventing the loss of TBK by documenting the medicinal traditions, passed down orally for centuries, in the words of the participants, shedding new light on the traditional knowledge of the inhabitants of the island. The findings lay the foundations for future applied studies in the fields of phytotherapy and phytochemical investigation.