Postprandial oxidative stress has been shown to promote atherosclerosis. Grape pomace (GP) is a source of similar-to-wine bioactive micro-constituents with known antioxidant properties. The aim of the present study was to evaluate metabolic and oxidative stress responses after the intake of grape pomace (GP) extract along with a high-fat meal, in normal and overweight healthy women. In a randomized, double-blind, placebo-controlled crossover study, 18 women were finally included, 11 with BMI < 25 kg/m2 and 7 with BMI > 25 kg/m2, and consumed a high-fat meal with placebo or GP extract capsules in two separate visits. Blood samples were collected before and 6 h after the consumption. Measurements included basic biochemical markers, uric acid (UA), protein carbonyls (PC), thiobarbituric acid substance (TBARS) levels, as well as superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. At certain time points, the GP extract consumption in normal-weight women reduced UA, TBARS levels, and SOD activity, whereas it increased UA and reduced PC levels in overweight/obese women, compared to the placebo. GP-derived bioactive compounds may exert antioxidant actions during the postprandial state in healthy women, through different mechanisms according to their BMI status.