Climate change will increase the occurrence of plants simultaneously suffering drought and pathogen stress. Although it is well-known that drought can alter the way plants respond to pathogens, the knowledge about the effect of concurrent drought and biotic stress in grapevine is scarce. This is especially true for Plasmopara viticola, the causal agent of grapevine downy mildew. This research addresses how vines with different drought tolerance respond to the challenge with P. viticola, drought stress or their combination, and how one stress affects the other. An artificial inoculation was performed on two cultivars, exposed to full or deficit irrigation, in the Mediterranean climate of Cyprus. In parallel, leaf disks from these plants were inoculated in controlled conditions. Leaves were sampled at an early infection stage to determine the influence of the single and combined stresses on oxidative parameters, chlorophyll and phytohormones. Under irrigation, the local Cypriot cultivar Xynisteri was more susceptible to P. viticola than the drought-sensitive Chardonnay. Drought stress increased their susceptibility in leaves inoculated in controlled conditions. Conversely, both cultivars showed resistance against P. viticola when inoculated in planta under continued deficit irrigation. Despite their resistance, the pathogen-associated responses in auxin, antioxidant enzyme activity and proline still occurred in these drought-stressed plants. Surprisingly, abscisic acid, rather than the generally implicated jasmonic and salicylic acid, seemed to play a prominent role in this resistance. The irrigation-dependent susceptibility highlights that the changing climate and the practices used to mitigate its effects, may have a profound impact on plant pathogens.