This study aimed to introduce innovation in the development of gluten-free bread, based on a combination of rice flour and a starch blend by optimizing the formulation of three different starches (corn, potato and tapioca) within a rice/corn formula and enriching it with natural flours (acorn, soy, chestnut, chickpea, millet and quinoa). Employing an extreme vertices mixture design, we optimized the subpart consisting of 30% (w/w) starch. Subsequently, the enriched gluten-free breads were subjected to comprehensive characterization, including the assessment of their physical, textural, rheological, antioxidant, color and sensory properties. Key findings revealed an optimal starch composition of 18 g w/w corn starch, 12 g w/w potato starch and 0 g w/w tapioca starch. Enriching the bread with quinoa, millet and chickpea flours allowed obtaining bread with a superior specific volume and a softer texture compared to other variants. Furthermore, substituting corn with various flours enhanced the antioxidant profile, with chestnut and soy flour-enriched bread exhibiting higher total phenolic content and acorn-enriched gluten-free bread demonstrating superior antioxidant activity. Sensory analysis indicated a preference for enriched breads over plain corn bread, particularly the variants enriched with quinoa and chestnut. The evaluation of crust and crumb showed that breads containing chestnut and acorn flour were significantly (p < 0.05) darker, which is appreciated by tasters due to its sensory appeal. Principal component analysis clustered groups of gluten-free breads with enhanced physical and textural properties (quinoa, millet, chickpea) and gluten-free breads with the best sensorial characteristics in another group (acorn and gluten-free breads with the best sensorial characteristics in another group (acorn and chestnut).