Drought is the major abiotic stress which contributes to the reduction in the productivity of soybeans in Brazil, especially in the savanna regions. Two parental genotypes contrasting in drought tolerance (Embrapa 48tolerant and BR 16-sensitive) were used to study the molecular mechanism underlying this process in soybeans. The hydric potential of the BR 16 reached values of −1.0 and −1.5 MPa, three days before the Embrapa 48, confirming the contrasting drought tolerance. The proteomic, phosphoproteomic and metabolomic profiles were evaluated to detect the metabolic pathways, which were affected by the drought stress. An integrative overview showed that the tolerant plants maintain cell homeostasis and the photosynthetic metabolism was unchanged under the stress condition in contrast to the sensitive genotype that showed several dysregulated pathways. These findings were confirmed by the protein expression and protein regulation by phosphorylation. Furthermore, just small deviations in the metabolic pathways were observed for drought-tolerant plants in comparison to the sensitive genotype. Complex post-translational modification patterns by phosphorylation were detected in some key enzymes, such as carbonic