In contrast to ultra-processed foods that are associated with increased weight gain and obesity risk, nutritionally engineered dietary supplements, including meal replacement (MR) bars and shakes, are generally promoted as healthy. Limited data is available comparing the metabolic and hunger responses of whole food (WF) versus MR meals. The purpose of this study was to directly compare the thermic effect (TEM), respiratory exchange ratio (RER), hunger/taste ratings, and glucose response of two different breakfast meals containing MR and WF products in young healthy women. Eight volunteers completed two iso-caloric (529 kcals)/macronutrient (50% carbohydrates; 26% fat; 24% protein) test meals in a single-blind, randomized crossover design: (1) whole food meal; or (2) meal replacement. TEM was significantly higher following MR compared with WF (percent mean difference: 7.76 ± 3.78%; absolute mean difference: 0.053 ± 0.026 kcal/minute, p = 0.048), whereas WF substrate utilization demonstrated lower carbohydrate oxidation (RER) than MR (mean difference: −0.024 ± 0.008, p = 0.005). No differences existed for blood glucose response and feelings of hunger, desire to eat, and satiety among trials. Consumption of an MR meal increases postprandial thermogenesis and RER compared to a WF meal, which may impact weight control and obesity risk over the long-term.