© 2020, Springer Science+Business Media, LLC, part of Springer Nature. Enhancing the productivity of biomass, carbohydrates, proteins, and lipids in microalgae cultures is an essential task to justify the feasibility of using biofuels as energetic alternatives to fossil fuels. Diverse strategies can be used to get a biologically plausible optimization of the microalgae culture such as using indigenous microalgae added with other microorganisms such as fungi or bacteria, analyzing the effect of culture broth composition and reaction experimental conditions. A wastewater isolated co-culture microalgae-yeast (CCMY) was evaluated as potential biomass and lipids-efficient producer. The Box-Behnken experimental design and the response surface methodology yield to identify the best attainable composition of inorganic nutrient variables in culture media: sodium nitrate (NaNO3), potassium phosphate (K2HPO4), and ferrous sulfate (FeSO4). The results of the experimental design revealed that the NaNO3, K2HPO4, and FeSO4 were three factors significantly influencing the biochemical content. The detected optimal conditions correspond to a highest biomass production of 1.68 g L−1; the carbohydrate content was 16.75%, for proteins 37.11%, and the maximum lipid content was 27.77%. These values were about two times higher than the results obtained with the original version of the culture broth (BBM). The complexity of inorganic salts effect on the biomass and lipid accumulation motivates the proposal of a quartic order mathematical model which characterizes the productivity of microalgae-yeast co-culture as function of the inorganic micronutrient contents.