Background: Despite major advances in the fight against this parasitic disease, malaria remained a major cause of concern in 2021. This infection, mainly due to Plasmodium falciparum, causes more than 200 million cases every year and hundreds of thousands deaths in the developing regions, mostly in Africa. The last statistics show an increase in the cases for the third consecutive year; from 211 million in 2015, it has reached 229 million in 2019. This trend could be partially explained by the appearance of resistanceto all the used antimalarials, including artemisinin. Thus, the design of new anti-Plasmodium compounds is an urgent need. For thousands of years, nature has offered humans medicines to cure their diseases or the inspiration for the development of new active principles. It then seems logical to explore the natural sources to find new molecules to treat this parasitosis.

Methods: Therefore, this review reports and analyzes the extracts (plants, bacteria, sponges, fungi) and the corresponding isolated compounds, showing antiplasmodial properties between 2013 and 2019.

Results and Conclusion: Nature remains a major source of active compounds. Indeed, 648 molecules from various origins, mostly plants, have been reported for their inhibitory effect on Plasmodium falciparum. Among them, 188 scaffolds were defined as highly active with IC₅₀ ≤ 5 μM, and have been reported here in detail. Moreover, the most active compounds showed a large variety of structures, such as flavonoids, triterpenes, and alkaloids. Therefore, these compounds could be an interesting source of inspiration for medicinal chemists; several of these molecules could become the next leads for malaria treatment.