Cosmos sulphureus Cav. (Asteraceae), and endemic plant of Mexico is used in herbal medicine. In this study, the phytochemical composition, phenolic content, and antioxidant activity of ethanolic and methanolic extracts from C. sulphureus leaves and flowers were determined. The phytochemical analysis showed the presence of compounds such as terpenoids, phenolic compounds, tannins, and flavonoids and the absence of alkaloids, saponins, glycosides, and anthraquinones. The experimental results showed that the extracts have high contents of phenolic, flavonoid, and condensed tannins contents. The phenolic compounds identified in the C. sulphureus extracts by high-performance thin-layer chromatography (HPTLC) include phenolic acids such as chlorogenic acid and caffeic acid as well flavonoids such as rutin and quercetin. The C. sulphureus extracts showed a relevant free radical scavenging activity, ferric-reducing antioxidant power, lipid peroxidation inhibition ability, and oxygen radical antioxidant capacity. This research highlights the phytochemical profile and antioxidant activity of phenolic compounds-rich extracts from C. sulphureus leaves and flowers.