Enhancing bioactive compounds with antioxidant activities has always been a pursuit of growers in the hydroponic production of lettuce in greenhouses with artificial lighting. Light-Emitting Diode (LED) lighting represents an effective lighting strategy that promotes the accumulation of bioactive compounds in lettuce by reducing dark periods under unfavorable meteorological conditions and extending the photosynthetic duration. In this study, the accumulation of bioactive compounds and their antioxidant activities, using lettuce-adapted growth technologies such as elevated oxygen concentration and elevated oxygen combined with LED red-blue light, were investigated. These technologies were compared to the control, which consisted of the natural oxygen concentration, in a controlled hydroponic system, for the two lettuce cultivars, Carmesi and Lugano. Our results demonstrate that lettuce grown under elevated oxygen combined with LED lighting exhibited increases of up to 48% in total phenolic content and up to 87% in total flavonoid content, depending on cultivar and growing season, compared to control growth technology. The highest antioxidant capacity was recorded under the EOC+LED growth technology, as confirmed by DPPH, FRAP, and CUPRAC assays. This study proposes an effective growth strategy for hydroponic lettuce cultivation that enhances bioactive compound accumulation and provides theoretical and technical guidance for energy-efficient greenhouse production.