Cadmium (Cd) and zinc (Zn) coexist in the environment but interact differently in plants. Cosmos bipinnatus has been potentially considered as a Cd-accumulator. Thus, this study investigated the detoxification mechanism in C. bipinnatus seedlings under Cd, Zn and Cd + Zn stresses. In the present study, the presence of Zn inhibited Cd uptake and translocation, whereas Cd merely hindered Zn uptake. The concentration of Cd in soluble fraction significantly decreased and Cd was bounded to the cell wall in root under Cd + Zn stress. Meanwhile, Zn and Cd mutually decreased their concentrations in the ethanol extractable form (F_E) and water extractable form (F_W) in roots and shoots. Furthermore, Cd + Zn stress enhanced the activities of superoxide dismutase (SOD, EC 1.15.1.1), peroxidase (POD, EC 1.11.1.7) and catalase (CAT, EC 1.11.1.6) compared to Cd stress alone. These results suggested that Zn effectively decreased Cd uptake and translocation, changed their subcellular distributions, regulated their chemical forms composition and increased antioxidative enzyme activities, thereby enhancing the tolerance to Cd in C. bipinnatus. This study physiologically revealed the interactive effect of Cd and Zn on the detoxification mechanism of Cd in C. bipinnatus and provided new information on phytoremediation of the heavy metal contaminated soils.