Oudemansiella raphanipes ethanolic extract (ORE) was prepared via ultrasonication-assisted ethanolic extraction and enriched through silica gel and macroporous adsorption resin chromatography to afford a non-/weakly polar fraction (ORE-S) and a polar fraction (ORE-N), respectively. This study aimed to (1) quantify major bioactive components (e.g., polyphenols, alkaloids, and terpenes) in ORE-S and ORE-N, (2) assess their antioxidant activities, (3) correlate compositional differences with antioxidant function, and (4) identify key antioxidant compounds along with their potential mechanisms of action. By integrating widely targeted metabolomics with network pharmacology, we not only elucidated how enrichment methods influence the antioxidant properties of ORE but also demonstrated the potential of ORE-N as a valuable source of bioactive compounds and natural antioxidants.