The possibility of breweŕs spent grain exploitation through a sequence of supercritical fluid extraction, acid hydrolysis, and fermentation was considered. All steps have been optimized within an interval of operative conditions, using specific designs of the experiments, and modeled through the Response Surface Methodology. The supercritical fluid extraction was optimized in the pressure range 20–40 MPa and temperature 40–100 °C. A fractional factorial design was applied considering the sulfuric (0.065–0.37 M) and nitric (0.01–0.5 M) acid concentration, and the liquid–solid ratio (8–12 w/w %) as independent factors for the hydrolysis step. The fermentation process of pre-treated BSG was also optimized using the Box-Behnken design with temperature (25–37 °C), inoculum volume (5–15 v/v %), and pH (4.5–6.5) as investigated factors. At optimal conditions, the overall process led to an ethanol yield of 82 % evaluated with respect to the theoretical one. Moreover, all the supercritical fluid extracts were richer in phenolic compounds than the ones obtained by the traditional Soxhlet method.