<p>Drought is a major natural disaster that affects plant growth. <i>Agropyron mongolicum</i> possesses a wide range of drought tolerance genes acquired during its long evolution and adaptation to harsh environments. However, the regulatory mechanisms for drought resistance in <i>A. mongolicum</i> are complex, limiting the development and utilization of gene resources in response to drought stress. In this study, we examined differences in morphological, physiological, metabolite and transcript levels between the drought-tolerant (T) and drought-sensitive (S) genotypes of <i>A. mongolicum</i> to identify key metabolites and genes associated with the drought response. The morphological and physiological results suggest that the S genotype is suppressed by drought stress to a greater extent than the T genotype. Based on the metabolome and transcriptome data, we identified that serine/threonine-protein kinase SRK2 (<i>SRK2</i>), peptide chain release factor subunit 1 (<i>eRF1</i>), glutamine synthetase (<i>GS</i>), polyphenol oxidase (<i>PPO</i>), and aspartyl protease family protein (<i>ASP</i>) were highly correlated with key metabolites such as L-γ-glutamyl-L-leucine and γ-glutamylphenylalanine in leaves by co-expression network analysis, and alcohol-forming fatty acyl-CoA reductase (<i>FAR</i>), DNA oxidative demethylase (<i>ALKBH</i>), GDSL esterase/lipase (<i>GELP</i>), beta-fructofuranosidase (<i>INV</i>), and glutamine synthetase (<i>GS</i>) were highly correlated with key metabolites such as Trp-Glu-Ile and citric acid diglucoside in roots. Moreover, we identified the potential involvement of fatty acid degradation and glycolysis/glucogenesis pathways in the enhancement of drought tolerance in <i>A. mongolicum</i>. This study provides a foundation for genetic engineering studies of drought resistance in Poaceae plants.</p>