This study aimed to investigate the alterations in plasma antioxidant activity after the consumption of a single oral dose of curcumin, vitamin C, and E administered individually or in combination to (i) assess possible synergies or antagonism between the antioxidants and (ii) determine the optimal composition of the antioxidant mixture such that the duration of action is prolonged to beyond that of individual antioxidants. Each antioxidant was administered to male Sprague-Dawley rats, and blood samples were drawn at different time points up to 180 min to measure the plasma total antioxidant capacity (TAC). Five antioxidant compositions (M1-M5) were evaluated to assess the possible synergies or antagonisms among them and to determine the optimal composition of the antioxidant mixture. Blood samples were collected up to 360 min post-consumption. A single oral dose of individual antioxidants significantly increased the TAC values; however, the time to reach the peak TAC value varied. Among the 5 antioxidant compositions, M2 exhibited the highest and most prolonged antioxidant effect in plasma; this was greater than the proportional sum of the effects of the individual antioxidants in the composition. This result indicates a synergistic interaction among antioxidants in the optimal composition M2.