This study intends to optimize the production and evaluation of the nutritional quality of composite flour comprising wheat and millet. The experimental design for the composite flour was laid down using the I-optimal mixture design of response surface methodology (RSM). With an extensive literature survey, wheat, finger millet, barnyard millet, and foxtail millet were selected to understand the health benefits of wheat flour. A total of 24 flour blends were prepared by incorporating wheat flour (40–85%), finger millet flour (5–20%), barnyard millet flour (5–20%), and foxtail millet (5–20%) as independent variables; however, the responses were protein, antinutrient (Tannin), and antioxidants (1,1-diphenyl 2-picryl hydrazyl). The statistical and numerical optimization technique of RSM was used to optimize multiple responses simultaneously. After optimization, eight distinct solutions were obtained using the software. Out of the eight solutions, the best optimum level of fortified mixture was selected and wheat (51.09%), finger millet (20%), barnyard millet (8.91%), and foxtail millet (20%) with protein content (23.19 mg g–1), antinutrient content (9.07 mg g–1), and antioxidant activity (61.52%), along with the highest desirability (0.845), were found to be the best. The optimized mixed flour obtained from wheat and millet blends had superior nutritional properties, making it an appropriate choice for consumers with dietary requirements, particularly those allergic to gluten. Furthermore, the optimized wheat–millet flour is suitable for large-scale production and can be used to improve consumers’ nutrient delivery and protein requirements. The study optimized composite flour through mixture design application and highlighted the applicability of RSM in the food industry. The outcome indicates that fortified flour finds its applicability in the food industry, particularly for products such as biscuits, noodles, pasta, and other bakery items.