Water deficit triggers physiological, biochemical, and molecular changes in leaves that could be important for overall plant adaptive response and it can affect tomato yield and quality. To assess the influence of long-term moderate drought on leaves, four tomato accessions from MAGIC TOM populations were selected on the basis of their differences in fruit size and were grown in a glasshouse under control and water deficit conditions. Drought affected stomatal conductance more in large fruit genotypes compared to cherry genotypes and this could be related to higher abscisic acid (ABA) leaf content. Compared to large fruits, cherry tomato genotypes coped better with water stress by reducing leaf area and maintaining photochemical efficiency as important adaptive responses. Accumulation of soluble sugars in the cherry genotypes and organic acid in the leaves of the larger fruit genotypes indicated their role in the osmoregulation and the continuum of source/sink gradient under stress conditions. Long-term moderate drought induced upregulation of NCED gene in all four genotypes that was associated with ABA production. The increase in the expression of ZEP gene was found only in the LA1420 cherry genotype and indicated its possible role in the protection against photooxidative stress induced by prolonged water stress. In addition, upregulation of the APX genes, higher accumulation of vitamin C and total antioxidant capacity in cherry genotype leaves highlighted their greater adaptive response against long-term drought stress compared to larger fruit genotypes that could also reflect at fruit level.