Recent studies underscore the therapeutic potential of citrus polymethoxylated flavonoids-such as tangeretin, sinensetin, and nobiletin-in attenuating inflammation, mitigating oxidative stress, and enhancing metabolic health in individuals with obesity. This randomized, double-blind, placebo-controlled clinical trial assessed the effects of a functional orange juice enriched with flavonoids (200 mL/day) combined with a low-calorie diet over six weeks in 44 obese participants. All subjects adhered to a hypocaloric diet and were randomly assigned to receive either flavonoid-enriched juice (n = 22) or placebo juice (n = 20). Both groups experienced significant reductions (p < 0.05) in weight, body mass index (BMI), fat mass, and waist circumference. However, the flavonoid-enriched juice group showed more pronounced improvements in metabolic biomarkers, including significant decreases in low-density lipoprotein cholesterol (LDL-C) and glycated hemoglobin (A1c) levels. Critically, the intervention enhanced systemic antioxidant defense, evidenced by increased total antioxidant capacity and upregulation of glutathione peroxidase 1 (GPX1), an essential enzyme that reduces hydrogen peroxide and lipid hydroperoxides. This suggests a direct impact on cellular redox homeostasis. Additionally, the enriched juice group exhibited reduced levels of pro-inflammatory cytokines interferon-gamma (IFN-γ) and tumor necrosis factor-alpha (TNF-α), indicating an anti-inflammatory effect. Favorable modulation of adipokines was also observed, with elevated adiponectin-a hormone associated with improved insulin sensitivity-and decreased leptin and plasminogen activator inhibitor-1 (PAI-1), both linked to obesity-related inflammation and thrombosis risk. These findings suggest that dietary supplementation with flavonoid-enriched orange juice, in conjunction with caloric restriction, can enhance antioxidant defenses, reduce inflammation, and improve key metabolic parameters in obese individuals.