Rhanterium epapposum Oliv. (Family: Asteraceae) is a common plant in Saudi Arabia, possessing a variety of traditional uses. The current targets were studying the comparative chemical profile and antioxidant of the essential oil (EO) of R. epapposum collected from a sandy habitat at Qareenah, Riyadh, Saudi Arabia. The EO profiling was constructed via gas chromatography-mass spectrometry (GC-MS) and GC-flame ionization detection (GC-FID). Forty-eight compounds were found, including monoterpenes (hydrocarbons 3.25% and oxygenated 48.64%), sesquiterpenes (hydrocarbons 12.64 % and oxygenated 32.38%), which are the backbone of the oil along with a minor of other non-terpenoid compounds (1.31%). Linalool (18.02%), α-eudesmol (11.98%), trans-sesquisabinene hydrate (11.63%), aromadendrene oxide-(1) (7.68%), nerol (6.88%), and α-terpineol (5.01%) were identified as the dominant components. The EO was evaluated for its antioxidant activity using in vitro DPPH, ABTS, and FRAP methods. The results demonstrated that R. epapposum EO possesses a dosage-dependent ability for antioxidant scavenging activity as per all three techniques. This EO exhibited IC50 values of 517.59, 350.24, and 713.72 μg/mL for the DPPH, ABTS, and FRAP, respectively, through the comparison with the ascorbic acid with respective values of 36.10, 26.12, and 44.58 μg/mL. The main compounds were subjected to docking analysis on cytochrome P450 1A1 and xanthine oxidase. All evaluated compounds exhibited good binding affinities especially α-eudesmol and linalool for both enzymes, respectively. The current research confirmed the potent free radical scavenging properties of R. epapposum EO. More research on the antioxidant content of this oil and/or its primary constituents in pure form on the two enzymes, cytochrome P450 1A1 and xanthine oxidase, is proposed to develop a better understanding of the oxidative action routes in vivo and in vitro.