Water stress causes considerable yield loss in potato, usually considered a drought-sensitive crop. Photosynthesis is a primary target of abiotic stresses, and manipulation of photosynthetic electron distribution in chloroplasts by introducing the alternative electron carrier flavodoxin increased tolerance of model plants to multiple environmental challenges including drought, suggesting that a similar strategy could function in crops. We show herein that expression of a plastid-targeted cyanobacterial flavodoxin in potato plants protected photosynthetic activities even at a pre-symptomatic stage of drought stress. Transcriptional profiling revealed that 5-6% of leaf-expressed genes were regulated by flavodoxin in the absence of stress, representing pathways modulated by chloroplast redox status during normal growth. The majority (68.5%) of drought-responsive genes were also affected by flavodoxin, whose main effect was to mitigate changes in gene expression caused by water deficit, suggesting that flavodoxin-expressing plants suffered less stress than their wild-type siblings, and accordingly displayed an attenuated response to the adverse condition. Expression of 290 drought-responsive genes was primed in the transformants in the absence of stress, and could contribute to drought tolerance. Yield improvement under chronic water limitation was moderate but significant in flavodoxin-expressing plants, indicating that the flavoprotein has potential to improve major agronomic traits in potato.