Solid-state fermentation of burdock roots with Eurotium cristatum was performed to enhance their functional properties. Fermentation induced marked compositional remodeling, resulting in a 1.37-fold increase in protein content compared to unfermented controls. Antioxidant capacities were markedly enhanced. DPPH and ABTS radical-scavenging activities both exceeded 90%, and intracellular ROS levels in Caenorhabditis elegans were reduced by 62.7%. Phenolic profiling via UPLC-ESI-MS/MS identified and quantified 74 phenolic compounds across samples; notably, 10 flavonoids were exclusively detected in fermented burdock roots, indicative of microbial biotransformation. Correlation analysis integrating phenolic abundance with all three antioxidant endpoints revealed 11 compounds significantly associated with enhanced bioactivity. Among these, sinapic acid, 3-hydroxyflavone, liquiritigenin, and sakuranetin exhibited positive correlations with all three antioxidant measures. Prostaglandin G/H synthase 1 (PTGS1) and PTGS2 were identified as shared antioxidant-relevant targets, with PTGS1 highlighted due to its constitutive role in prostaglandin biosynthesis. Importantly, 3-hydroxyflavone, liquiritigenin, and sakuranetin were newly emerged following fermentation, providing direct evidence that E. cristatum mediates the synthesis or structural modification of key flavonoids, thereby augmenting the antioxidant chemical profile and functional efficacy of burdock roots.