Drought tolerance varies among different peanut (Arachis hypogaea L.) cultivars. Here, drought responses of two cultivars, Huayu 22 (HY22) with drought tolerance and Fuhua 18 (FH18) with drought sensitivity, were compared at the morphological, physiological, biochemical, photosynthetic, and transcriptional levels. Drought stress caused wilting and curling of leaves, bending of stems, and water loss in both cultivars. There was an increase in malondialdehyde (MDA) content under prolonged drought stress, more so in FH18. But the levels of reactive oxygen species (H₂O₂) and lipid peroxidation were low in HY22. The activities of superoxide dismutase (SOD), peroxidase (POD), and glutathione reductase (GR) were considerably elevated, corresponding with rapid increases in the accumulation of soluble proteins, soluble sugars, and proline. Transcriptional sequencing showed gene expression varied seriously in HY22, which was upregulated in both stems of two cultivars, though downregulation was less pronounced in HY22. KEGG pathway analysis revealed significant enrichment in four leaf and six stem pathways. Additionally, core genes relating to photosynthesis, carbon fixation, proline synthesis, and sucrose and starch synthesis pathways were identified by correlation analysis. Those gene expressions were variously upregulated in stems of two cultivars, especially in HY22, giving a novel view of the shoot as a whole participating in stress response.