The economic sustainability of microalgae-based processes is still a major issue hindering the industrial application of such technologies. In this work, a mathematical model describing microalgae in varying light and temperature conditions is used to propose an optimized operation policy to increase productivity. The model is calibrated experimentally to describe the growth of Scenedesmus sp. cultivated in two outdoor pilot photobioreactors with different volumes and then used to maximize algal biomass productivity by proposing a new harvesting policy of the culture. Experimental tests showed that a significant productivity increase is achievable using the optimized procedure. Simulated tests also highlighted that the additional implementation of an optimal temperature control strategy may lead to double biomass production.