The present study was focused on lettuce, a widely consumed leafy vegetable for the large number of healthy phenolic compounds. Two differently-pigmented lettuce cultivars, i.e. an acyanic-green leaf cv. and an anthocyanic-red one, were grown under high light intensity or elevated CO2 or both in order to evaluate how environmental conditions may affect the production of secondary phenolic metabolites and, thus, lettuce quality. Mild light stress imposed for a short time under ambient or elevated CO2 concentration increased phenolics compounds as well as antioxidant capacity in both lettuce cvs, indicating how the cultivation practice could enhance the health-promoting benefits of lettuce. The phenolic profile depended on pigmentation and the anthocyanic-red cv. always maintained a higher phenolic amount as well as antioxidant capacity than the acyanic-green one. In particular, quercetin, quercetin-3-O-glucuronide, kaempferol, quercitrin and rutin accumulated under high light or high CO2 in the anthocyanic-red cv., whereas cyanidin derivatives were responsive to mild light stress, both at ambient and elevated CO2. In both cvs total free and conjugated phenolic acids maintained higher values under all altered environmental conditions, whereas luteolin reached significant amounts when both stresses were administered together, indicating, in this last case, that the enzymatic regulation of the flavonoid synthesis could be differently affected, the synthesis of flavones being favored.