This study aimed to determine the effect of the extrusion process on the nutritional and bioactive profiles of brewer’s spent grain (BSG), contributing to nutrition security by applying a circular economy concept. Response surface methodology was used to optimize the effect extrusion parameters (moisture content, screw speed, and barrel temperature ) had on BSG’s soluble dietary fiber, free glucose, and overall antioxidant capacity. Proximate composition analyses, amino acid profile, extractable polyphenolic content, and antioxidant capacity of BSG and brewer’s spent grain extruded under optimal conditions (BSGE) were carried out. Food safety was analyzed by their microbiological quality, gluten, and acrylamide content. Optimal extrusion conditions were 15.8% of moisture content, 164.3 revolutions per min and 122.5 ◦C. BSGE presented 61% more soluble dietary fiber than BSG, lower digestible starch, 0.546% of free glucose, and protein quality parameters mostly like those reported for egg, soy, and milk. Despite this, BSG’s overall antioxidant capacity was not improved after thermomechanical processing; BSGE had significantly higher extractable polyphenolic content in its alkali extracts, which were determined qualitatively by high-performance liquid chromatography quadrupole time-of-flight assay in its hydro-alcoholic acid extracts. Furthermore, although it is not gluten free, BSGE is a safe food ingredient with acceptable microbiological quality and no acrylamide.