Adequate antioxidant supply is essential for maintaining metabolic homeostasis and reducing oxidative stress during detoxification. The emerging evidence suggests that certain classes of phytonutrients can help support the detoxification process by stimulating the liver to produce detoxification enzymes or acting as antioxidants that neutralize the harmful effects of free radicals. This study was designed to examine the effects of a guided 28-day metabolic detoxification program in healthy adults. The participants were randomly assigned to consume a whole food, multi-ingredient supplement (n= 14, education and intervention) or control (n= 18, education and healthy meal) daily for the duration of the trial. The whole food supplement contained 37 g/serving of a proprietary, multicomponent nutritional blend in the form of a rehydratable shake. Program readiness was ensured at baseline using a validated self-perceived wellness score and a blood metabolic panel, indicating stable emotional and physical well-being in both groups. No significant changes or adverse effects were found on physical or emotional health, cellular glutathione (GSH) and the GSH:GSSG ratio, porphyrin, and hepatic detoxification biomarkers in urine. The intervention was positively associated with a 23% increase in superoxide dismutase (p= 0.06) and a 13% increase in glutathione S-transferase (p= 0.003) activities in the blood. This resulted in a 40% increase in the total cellular antioxidant capacity (p= 0.001) and a 13% decrease in reactive oxygen species (p= 0.002) in isolated PBMCs from participants in the detoxification group. Our findings indicate that consuming a whole food nutritional intervention as a part of the guided detoxification program supported phase II detoxification, in part, by promoting enhanced free radical scavenging and maintaining redox homeostasis under the body’s natural glutathione recycling capacity.