Combination of stresses often induce specific molecular responses in plants, which could not be predicted from the effects of the same stresses applied individually. Sulfur availability in soils affects both yield and seed quality in major crops, and the plant capacity to tolerate other environmental constraints. To dissect the molecular responses to sulfur deficiency, and how water deficit alters the effects, we employed a multi-omics approach in leaves of Pisum sativum, in which both yield and seed quality are compromised by these two stressors. Using transcriptomics, proteomics and gene co-expression network analyses, we identified a module of genes strongly driven by S availability. This includes known and putative new players of plant responses to S-deprived conditions. Conserved profiles between proteins and mRNAs were specifically observed within this module, suggesting transcriptional regulation. Under stress combination, plant growth was severely compromised, and molecular responses were amplified, notably at the transcriptome level, in a time-specific manner. Transcriptional regulators of the highlighted genes and pathways were predicted, which may represent interesting targets to develop crops tolerant to multi-stress conditions. The produced datasets also represent important resources for our knowledge of the plant molecular responses specifically induced under single or combined stresses in plants.