Drought negatively impacts the morphological, physiological, and molecular characteristics of plants. Here we performed quantitative proteomic and peptidomic analysis of spring wheat (Triticum aestivum L.). leaves and roots under drought stress conditions. Using isobaric tags for relative and absolute quantitation (iTRAQ), we identified 497 and 157 differentially expressed (DE) proteins in leaves and roots, respectively. The upregulated DE proteins in leaves were primarily involved in stress responses, such as oxidative stress and heat response, while those in roots were associated with metabolic processes like UDP-glucose metabolism and glutamine biosynthesis. Using peptidomic approaches, we identified 2294 endogenous extracellular peptides, including members of 16 small secreted peptides (SSPs) families, in the root secretome. In the stress-induced secretomes, we identified endogenous peptides, derived from proteins involved in cell wall catabolism and detoxification and involved in intercellular signaling and stress response. Identification of proteins and secretome peptides regulating the drought stress response helps to understand adaptation mechanisms and develop new agricultural technologies to increase productivity.