Melatonin (N-acetyl-5-methoxytryptamine) plays an essential role in abiotic stress in plants, but its mechanism in drought tolerance is unclear. To better understand the protective roles of melatonin against drought stress, we investigated the effect of foliar application with exogenous melatonin on plant growth, physiological responses, and antioxidant enzyme activities in rice seedlings under drought stress. Rice seedlings were grown for 21 days, and foliar sprayed with 0, 50, 100, 200, and 300 µM melatonin. The control plant was watered daily, while the others were subjected to drought stress by withholding water for seven days. The results showed that drought stress significantly reduced plant growth, relative water content, and chlorophyll content. Electrolyte leakage, malondialdehyde (MDA) content and hydrogen peroxide (H2O2) were also negatively affected by drought stress. Application of melatonin alleviated the effects of drought stress by increasing plant growth, improving relative water content and chlorophyll content, and decreasing electrolyte leakage, MDA, and H2O2. Foliar application with melatonin also increased antioxidant enzyme activities, including superoxide dismutase (SOD), catalase (CAT), ascorbate peroxidase (APX), and guaiacol peroxidase (GPX). In addition, melatonin also enhanced proline and total soluble sugar accumulation during drought stress. It is, therefore, suggested that foliar application with 100 µM melatonin was the most effective for reducing the adverse effects of drought stress in rice plants.