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Guarana (Paullinia cupana) is a plant from the Amazon region with cultural importance. Despite its early ancestral use by indigenous tribes, the first reports regarding the benefits of guarana consumption for human health were published in the 19th century. Since then, the use of guarana seed in powder and extract forms has been studied for its diverse effects on human health, such as stimulating, anti-inflammatory, antioxidant, anticancer, hypocholesterolemic, and anti-obesity effects. These effects are attributed to the high content of bioactive compounds found in guarana seeds, especially methylxanthines and flavonoids. In fact, the Brazilian Food Supplement Law has officially acknowledged guarana as a source of bioactive compounds. The number and diversity of studies focused on guarana and human health are increasing; thus, organizing and describing the available evidence on guarana and its applications is necessary to provide a framework for future studies. In this narrative review, we have organized the available information regarding guarana and its potential effects on human health. Guarana produces unique fruits with great potential for human health applications. However, the available evidence lacks human studies and mechanistic investigations. Future studies should be designed considering its applicability to human health, including intake levels and toxicity studies.