Solenostemma argel (Asclepiadaceae) is a beneficial folk medicine used to treat many diseases, including the kidney, liver, and stomach diseases. The aim of this study was to assess the anti-Staphylococcus aureus activity of an aqueous ethanolic extract of Solenostemma argel (AEESA) and identify its phenolic and volatile compounds using high-performance liquid chromatography (HPLC) and gas chromatography-mass spectroscopy (GC-MS). As revealed using the disc diffusion test and DNA cleavage analysis, S. argel extract was active against Staphylococcus aureus. The minimum inhibitory concentration (MIC) was 31.6 g/mL. Sixteen phenolic compounds of AEESA were analyzed using HPLC, wherein the phenolic compounds: pyrocatechol (9519.95 µg/g), ferulic acid (3221.41 µg/g), chlorogenic acid (3221.41 µg/g), and gallic acid (2730.85 µg/g) were the most abundant. Additionally, naringenin (2262.80µg/g) and quercetin (1750.25µg/g) were the major flavonoids. GC-MS analysis of AEESA revealed 30 volatile compounds, the major percentages of 9,12-octadecadienoic acid (z,z)-, methyl ester (33.44%), ascorbic acid 2,6-dihexadecanoate (7.22%), and butylated hydroxytoluene(5.46%), followed by 2-Pentadecanone, 6,10,14-trimethyl (4.77%), 2-Pentadecanone, 6,10,14-trimethyl (3.35%), Stigmasta-5,22-dien-3-ol, and acetate (3.Beta; 3.35%). The application of S. argel extract in reducing the growth of biofilms would subsequently diminish the development of antibiotic resistance and promote the future uses of plant extract components.