Sulfur availability in soils affects both yield and seed quality in major crops, and the plant capacity to tolerate environmental constraints. Under stress combination, plants often show specific responses at the molecular level. To dissect the molecular responses to sulfur deficiency in interaction or not with water deficit, a multi-omics approach was used focusing on the leaves of pea (Pisum sativum), at several days during the early reproductive phase. Using ionomics, transcriptomics, proteomics and gene network analyses, we identified a module of genes strongly driven by sulfur availability. This includes known and putative new players of plant responses to sulfur-deprived conditions. Conserved profiles between proteins and mRNAs were specifically observed within this module, suggesting transcriptional regulation. While moderate water deficit had little impact when occurring alone, it thoroughly perturbed plant growth and the leaf transcriptome and proteome when combined with sulfur deficiency. Under this stress combination, molecular responses were amplified, notably at the transcriptome level, in a time-specific manner. Genes with specific or greater responses under this condition were identified, and transcriptional regulators of the highlighted genes and pathways were predicted, which may represent interesting targets to develop crops tolerant to multi-stress conditions.