Sprouting is an effective treatment for improving nutritional and bioactive properties as well as lowering the anti-nutritional compounds in pseudo-cereals. Enhancing nutritional properties when using sprouted pseudo-cereals flours as a baking ingredient requires tailored formulation. Simplex centroid designs and response surface methodology has been applied in the present study to define the ideal proportions of ternary blends of sprouted kiwicha (SKF), cañihua (SCF) and wheat flours (WF) to simultaneously enhance the content in bioactive compounds (γ-aminobutyric acid, GABA, total soluble phenolic compounds and TSPC), as well as sensory (odor, color, taste and texture) and functional attributes (antioxidant activity, AA) while reducing phytic acid (PA) content of bread. The effect of gastric and intestinal digestion on bioactive compounds, AA, PA and starch hydrolysis was also evaluated. Mixture design allowed for the identification of optimal formulation (5% SKF, 23.1% SCF, 71.9% WF) that can be used to obtain breads with higher content of GABA, TSPC, AA, overall sensorial acceptability (scores > 7) and reduced PA content and glycemic index. Moreover, this study demonstrated that these nutritional and health benefits provided by the replacement of WF by sprouted pseudo-cereal flours remained upon digestion. The results of this study indicated that WF replacement with SKF and SCF is sensory acceptable and improved the nutritional quality of bread.