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<i>Lantana rhodesiensis</i> Moldenke is a plant widely used to treat diseases, such as rheumatism, diabetes, and malaria in traditional medicine. To better understand the traditional uses of this plant, a phytochemical study was undertaken, revealing a higher proportion of polyphenols, including flavonoids in <i>L. rhodesiensis</i> leaf extract and moderate proportion in stem and root extracts. The antioxidant activity of the extracts was also determined using three different assays: the radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, the FRAP method (Ferric-reducing antioxidant power) and the β-carotene bleaching test. The anti-malarial activity of each extract was also evaluated using asexual erythrocyte stages of <i>Plasmodium falciparum</i>, chloroquine-sensitive strain 3D7. The results showed that the leaf extract exhibited higher antioxidant and anti-malarial activities in comparison with the stem and root extracts, probably due to the presence of higher quantities of polyphenols including flavonoids in the leaves. A positive linear correlation was established between the phenolic compound content (total polyphenols including flavonoids and tannins; and total flavonoids) and the antioxidant activity of all extracts. Furthermore, four flavones were isolated from leaf dichloromethane and ethyl acetate fractions: a new flavone named rhodescine (5,6,3′,5′-tetrahydroxy-7,4′-dimethoxyflavone) (<b>1</b>), 5-hydroxy-6,7,3′,4′,5′-pentamethoxyflavone (<b>2</b>), 5-hydroxy-6,7,3′,4′-tetramethoxyflavone (<b>3</b>), and 5,6,3′-trihydroxy-7,4′-dimethoxyflavone (<b>4</b>). Their structures were elucidated by ¹H, ¹³CNMR, COSY, HSQC, HMBC, and MS-EI spectral methods. Aside from compound <b>2</b>, all other molecules were described for the first time in this plant species.