PC is a bioactive and colorant compound widely sought in the food, nutraceutical and cosmetic industries, and one of the most important pigments produced by Synechocystis salina . However, the general extraction process is usually time-consuming and expensive, with low extraction yields—thus compromising a feasible and sustainable bioprocess. Hence, new extraction technologies (e.g., ultrasound assisted-extraction or UAE) emerged in the latest years may serve as a key step to make the overall bioprocess more competitive. Therefore, this study aimed at optimizing the yields of phycocyanin (PC) rich-extracts of S. salina by resorting to UAE; in attempts to explore this process in a more economically feasible way; valorization of the remaining cyanobacterial biomass, via extraction of other bioactive pigments and antioxidants, was tackled within a biorefinery perspective. A two-stage extraction (using ethanol and water) was thus performed (because it favors PC extraction); other bioactive pigments, including chlorophyll a (chl a), carotenoids, and other phycobiliproteins (PBPs), but also antioxidant (AOX) capacity and extraction yields were also evaluated for their optimum UAE yields. A factorial design based on Box–Behnken model was developed; and the influence of such extraction parameters as biomass to solvent ratio (B/S ratio = 1.5-8.5 mg·mL−1), duty cycle (DT = 40-100%), and percentage of amplitude (A = 40-100%) were evaluated. The model predicted higher PC yields with high B/S ratio = 6 mg·mL−1, lower DT = 80% and an A=100%. Classical extraction was compared with UAE under the optimum conditions found; the latter improved PC yields by 12.5% and 47.8%, when compared to freeze-thawing extraction, and bead beater homogenization-based extraction, respectively. UAE successive extractions allowed to valorize other important bioactive compounds than PC, by reusing biomass, supporting a favorable contribution to the economic feasibility of the S. salina-based process towards a biorefinery approach.