The evolution of maize yields under drought is of particular concern in the context of climate change and human population growth. However, the multiplicity and versatility of drought-response mechanisms make the design of new drought-tolerant varieties a complex task that would greatly benefit from a better understanding of the genotype-phenotype relationship. To provide novel insight into this relationship, we applied a systems genetics approach integrating high-throughput phenotypic, proteomics and genomics data acquired on 254 maize hybrids grown under two watering conditions. Using association genetics and protein co-expression analysis, we detect more than 19,000 pQTLs across the two conditions and confidently identify nine loci with potential pleiotropic effects on the proteome. We show that water deficit, even mild, induced a deep proteome remodeling, which affected the structure of the protein co-expression network, and a reprogramming of the genetic control of the abundance of many proteins, notably those involved in stress response. Co-localizations between pQTLs and QTLs for ecophysiological traits, found mostly in the water deficit condition, indicate that this reprogramming may also affect the phenotypic level. Finally, we identify several candidate genes potentially responsible for both the co-expression of stress response proteins and the variations of ecophysiological traits under water deficit. Taken together, our findings provide novel insights into the molecular mechanisms of drought tolerance and highlight some pathways for further research and breeding.