Drought stress is one of the potent abiotic stress limiting cassava (Manihot esculenta) yield globally, but studies addressing both physiological and proteomic responses that how cassava crops can adjust their growth and metabolism under drought conditions are lacking. Combining leaf physiological and proteomic characteristics strongly allied with drought tolerance should results in enhanced drought tolerance in cassava crop. Therefore, the aims of this study were to explore the plant physiological and proteomic mechanisms involved in drought adaptation in cassava. Xinxuan 048 (XX048) was exposed to well-watered control (CK, relative soil water content (RSWC) as 80 ± 5%), mild drought stress (LD, RSWC as 65 ± 5%), moderate drought stress (MD, RSWC as 50 ± 5%) and severe drought stress (SD, RSWC as 35 ± 5%) from 30 days after planting. Under drought stress conditions, cassava plant showed a substantial decline in plant height, stem diameter, leaf number, leaf water content, the ratio of free water content to bound water content of leaf (FW/BW), net photosynthetic rate (Pn), intercellular CO2 concentration (Ci), stomatal conductance (Gs) and transpiration rate (Tr) compared with well watered plants. However, compared with control, leaf water content, SPAD value, cell membrane permeability, malondialdehyde (MDA), soluble sugar, protein proline content SOD and CAT activity were at peak under drought stress. The proteomic analysis revealed that among 3 339 identified proteins, drought stress increased and decreased abundance of 262 and 296 proteins, respectively, compared with control condition. These proteins were involved in carbohydrate energy metabolism, protein homeostasis, transcription, cell structure, cell membrane transport, signal transduction, stress and defense responses. These data not only provides a comprehensive dataset on overall proteomic changes in cassava leaves under drought stress, but also highlights the mechanisms by which euphorbiaceae plants can adapt to drought conditions.