Synechocystis salina is a cyanobacterium that has biotechnological potential thanks to its ability to synthesize several bioactive compounds of interest. Therefore, this study aimed to find optimal conditions, in terms of temperature (15–25 °C), pH (6.5–9.5), and NaCl concentration (10–40 g·L−1), using as objective functions the productivities of biomass, total carotenoids, total PBPs, phycocyanin (PC), allophycocyanin (APC), phycoerythrin (PE), and antioxidants (AOXs) capacity of Synechocystis salina (S. salina) strain LEGE 06155, based in factorial design resorting to Box-Behnken. The model predicted higher biomass productivities under a temperature of 25 °C, a pH of 7.5, and low NaCl concentrations (10 g·L−1). Maximum productivities in terms of bioactive compounds were attained at lower NaCl concentrations (10 g·L−1) (except for PE), with the best temperature and pH in terms of carotenoids and total and individual PBPs ranging from 23–25 °C to 7.5–9.5, respectively. PE was the only pigment for which the best productivity was reached at a lower temperature (15 °C) and pH (6.5) and a higher concentration of NaCl (≈25 g·L−1). AOX productivities, determined in both ethanolic and aqueous extracts, were positively influenced by lower temperatures (15–19 °C) and higher salinities (≈15–25 g·L−1). However, ethanolic AOXs were better recovered at a higher pH (pH ≈ 9.5), while aqueous AOXs were favored by a pH of 8. The model showed that biomass production can be enhanced by 175% (compared to non-optimized conditions), total carotenoids by 91%, PC by 13%, APC by 50%, PE by 130%, and total PBPs by 39%; for AOX productivities, only water extracts exhibited a (marginal) improvement of 1.4%. This study provided insightful information for the eventual upgrading of Synechocystis salina biomass in the biotechnological market.