In many developing countries human health problems are solved using local plants. Knowledge of their chemical composition and biological activities can contribute to the creation of natural-based products usefully employed in human health. In this work, we analyzed Paederia grandidieri leaves extracted with diverse eco-compatible procedures and subjected to chemical, microbiological, and cellular compatibility assays. Fresh leaves of P. grandidieri were harvested in southern Madagascar, dried and powdered. Distilled water and ethanol at different temperatures and times were used for extraction. Polyphenol composition, antioxidant, antibacterial, prebiotic and cytotoxic properties of the extracts were analyzed. The aqueous extracts contained higher levels of flavan-3-ols and flavanones, while the hydro-alcoholic extracts were richer in flavonols and flavones. The aqueous extracts showed the highest total phenolic and total flavonoid contents, and antioxidant activity, but lower cytotoxicity with respect to the hydro-alcoholic extracts. None of the extracts had significant antibacterial effects against selected oral pathogens, but prebiotic effects against Streptococcus salivarius were detected. This study indicates that P. grandidieri possesses significant biological properties which make it a suitable candidate for the production of pro-health products for the oral cavity.