Aim: Santolina chamaecyparissus L. (Asteraceae), commonly known as cotton lavender, is a small medicinal herb widely used in folk medicine, especially in North Africa and Europe. Thus, this study aimed to investigate the phytochemical and the antioxidant properties of S. chamaecyparissus methanol extract of leaves. Materials and Methods: Extraction was done by maceration method using absolute methanol as solvent. The extract was analyzed for its antioxidant capacity in different systems including free radical scavenging, superoxide anion radical scavenging, and reducing power activity. These various antioxidant activities were compared to standard antioxidants such as butylated hydroxy-anisole, butylated hydroxy-toluene, and Trolox. Moreover, phenolic compounds were detected by Liquid chromatography time-of-flight mass spectrometry. Results: Results showed that the methanol leaf S. chamaecyparissus extract exhibited significant (P < 0.001) antioxidant activity. The extract showed significant free radical scavenging activities in 1,1-diphenyl-2-picryl-hydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulphonic acid and superoxide radical scavenging antioxidant assays compared to standard. This inhibition is in a dose-dependent manner. The extract also showed strong reducing power. The Phytochemical analysis revealed the presence of phenolic acids and flavonoids in the methanol extract of the leaves of S. chamaecyparissus. The extract contained caffeic acid, p-coumaric acid, luteolin-7-O-glucoside, rutin, luteolin, and quercetin. Among the phenolic compounds, luteolin 7-glucoside, luteolin, and rutin are present predominantly in the extract. In addition, the total phenolic compounds and flavonoids were determined as gallic acid and quercetin equivalents, respectively. The total phenolic content was determined as 156.4 mg/g of gallic acid equivalent and the extract showed high total flavonoid content with the values of 32.8 mg/g of quercetin equivalent. Conclusion: According to the obtained results, it was concluded that phenolic compounds and flavonoids might contribute to high antioxidant activities of S. chamaecyparissus leaves.