The use of cultivars adapted to the climate and soil conditions associated with adequate irrigation supply maximizes lettuce agronomic performance. The aim of this work was to evaluate the agronomic performance of four lettuce cultivars submitted to five different drip irrigation depths under a protected environment in Viçosa-MG, Brazil. A randomized block design was applied in a split plot scheme with four replications, and several agronomic characteristics were evaluated by analysis of variance, Tukey range tests, regression and principal component analysis. A higher chlorophyll concentration in the Raider Plus cultivar promoted the production of more leaves, leading to a higher phytomass. The Luara cultivar presented a higher number of commercial leaves per plant than the other cultivars, regardless of the irrigation depth, reflected in a larger diameter and volume of the aerial part of the plants. The Raider Plus and Luara cultivars presented better root development than that of the other cultivars, reducing the effect of plant water stress even under lower irrigation depth conditions. Although higher water productivity (WP) was observed for the lowest irrigation depth (50% of ETc), important variables reached the maximum values at depths higher than 100% water replenishment. Therefore, Raider Plus and Luara cultivars with an irrigation depth of 110% of crop evapotranspiration provided better commercial lettuce quality and are recommended for lettuce cultivation in the research region and under conditions similar to those of the present study.