Cadmium (Cd) pollution is thought to be one of the leading threat to the environment due to its high toxicity. However, the molecular responses induced by Cd have so far been grossly overlooked. This study examines the morpho-physiological alterations combined with proteome changes in leaves of Sorghum bicolor when exposed to Cd. Ten days old sorghum seedlings were exposed to different concentrations (0, 100, and 150 μM) of CdCl2 and a significant accumulation of Cd in the leaves was recorded by ICP analysis. Furthermore, the effects of Cd exposure on protein expression patterns in S. Bicolor was investigated by two-dimensional gel electrophoresis (2-DE) and the 2-DE profile of leaf proteins from both control and Cd-treated seedlings were compared quantitatively using Progenesis SameSpot software. Results lined to morphological changes that plants treated with Cd suffered reduction of growth. The concentration of Cd was markedly reversed by the Cd treatments, whereas the absorption degree of Cd was increased by the higher concentration of Cd by confocal microscopy. Using 2-DE method, a total of 33 differentially expressed protein spots were identified by MALDI-TOF-TOF mass spectrometry. Of those, 13 protein spots were significantly enhanced/reduced while 20 reduced under Cd treatment. The most of the up-regulated proteins are involved in oxidative response, glutathione and sulfur metabolism as well as the secondary metabolite biosynthesis. Collectively, our study provides insights into the integrated molecular mechanisms of early responses to Cd and growth and physiological characteristics of sorghum seedlings hoping to provide references on the mechanism of heavy metal damaging plants.