The study of the relationship between cultivated plants and environmental factors can provide information ranging from a deeper understanding of the plant biological system to the development of more effective management strategies for improving yield, quality, and sustainability of the produce. In this article, we present a comprehensive metabolomics dataset of two phytochemically divergent lettuce (Lactuca sativa L.) butterhead varieties under different growing conditions. Plants were cultivated in hydroponics in a growth chamber with ambient control. The pre-harvest factors that were independently investigated were light intensity (two levels), the ionic strength of the nutrient solutions (three levels), and the molar ratio of three macroelements (K, Mg, and Ca) in the nutrient solution (three levels). We used an untargeted, mass-spectrometry-based approach to characterize the metabolomics profiles of leaves harvested 19 days after transplant. The data revealed the ample impact on both primary and secondary metabolism and its range of variation. Moreover, our dataset is useful for uncovering the complex effects of the genotype, the environmental factor(s), and their interaction, which may deserve further investigation.