Sweetpotato (Ipomoea batatas [L.] Lam) is a widely cultivated food crop with generally good adaptability. However, drought stress can cause a significant decline in yield. To reveal the response mechanism of sweetpotato to drought stress, an integrated physiological, proteomic and metabolomic investigation was conducted in leaves of two sweetpotato varieties with differing responses to drought stress, drought-resistant Wanzishu56 (WZ56) and a more sensitive variety, Ningzishu2(NZ2). Physiological analysis showed that the variety with better drought tolerance had superior performance in water retention capacity and photosynthetic efficiency under drought stress. A total of 1140 proteins were identified within the two varieties. Among them, 192 differentially expressed proteins were detected under drought conditions, including 97 that were up-regulated. Functional analysis showed that these up-regulated proteins were primarily involved in photosynthesis, reactive oxygen species metabolism, organonitrogen compound metabolism, and precursor metabolite catabolism and energy generation. All differentially expressed proteins in WZ56 that were involved in photosynthetic and glutathione metabolic processes were up-regulated. Enzyme activity assays were carried out to validate the proteomics data. Moreover, 75 metabolites were found to have a higher expression level in WZ56 than NZ2 under drought stress. The higher concentration of carbohydrates, amino acids, flavonoids and organic acids found in drought-stressed leaves of WZ56 suggested that these metabolites may improve the drought resistance of sweetpotato. This study uncovered specific-proteins and metabolites associated with drought resistance, providing new insights into the molecular mechanisms of drought tolerance in sweetpotato.