Cinchonains are a group of naturally occurring flavonolignans that exhibit a plethora of biological activities. This comprehensive review provides a critical analysis of the research on cinchonains and their related compounds, aiming to describe their various biological activities, including but not limited to, cytotoxicity, antioxidant, anti-inflammatory, antimicrobial, neuroprotective, antidiabetic, and anticancer activities. The occurrence and distribution of cinchonains in plants, their biosynthesis pathways, bioavailability, toxicity, and clinical investigations are also discussed. By synthesizing information from scientific literature, we present an informative and accessible overview of cinchonains' potential as a source of new therapeutics and highlight the importance of continued research on cinchonains and their related compounds to unlock their possible therapeutic merits.