Plant production is crucial for space journeys self-autonomy by contributing to the dietary intake necessary to sustain the physical and psychological well-being of space colonists, as well as for contributing to atmospheric revitalization, water purification and waste product recycling. Choosing the appropriate cultivar is equally important as the species selection, since cultivar influences the obtained fresh biomass, water use efficiency (WUE), growing cycle duration, qualitative features and postharvest performance. Two differently pigmented butterhead Lactuca sativa L. (red and green Salanova) cultivars were assessed in terms of morphometric, mineral, bioactive and physiological parameters. The experiment was carried out in a controlled environment growth chamber using a closed soilless system (nutrient film technique). Red Salanova registered a biomass of 130 g at harvest, which was 22.1% greater than green Salanova, and a water uptake of 1.42 L during the full growing period corresponding to WUE of 91.9 g L-1, which was 13.8% higher than that of green Salanova. At harvest, green Salanova had accumulated more P, K, Ca, Mg and 37.2% more nitrate than red Salanova, which however had higher relative water content, leaf total and osmotic potential and higher SPAD index. Red Salanova also exhibited at harvest around two-fold higher lipophilic antioxidant activity and total phenols, and around six-fold higher total ascorbic acid levels. These latter characteristics improved the antioxidant capacity of red Salanova enabling it to use light more efficiently and deliver better overall performance and yield than green Salanova. Moreover, the higher phenolics and total ascorbic acid contents of red Salanova constitute natural sources of antioxidants for enriching the human diet and render it an optimal candidate cultivar for near-term missions.