Calotropis gigantea is often found in mining areas with heavy metal pollution. However, little is known about the physiological and molecular response mechanism of C. gigantea to Cd stress. In the present study, Cd tolerance characteristic of C. gigantea and the potential mechanisms were explored. Seed germination test results showed that C. gigantea had a certain Cd tolerance capacity. Biochemical and transcriptomic analysis indicated that the roots and leaves of C. gigantea had different responses to early Cd stress. A total of 176 and 1618 DEGs were identified in the roots and leaves of C. gigantea treated with Cd compared to the control samples, respectively. Results indicated that oxidative stress was mainly initiated in the roots of C. gigantea, whereas the leaves activated several Cd detoxification processes to cope with Cd, including the upregulation of genes involved in Cd transport (i.e., absorption, efflux, or compartmentalization), cell wall remodeling, antioxidant system, and chelation. This study provides preliminary information to understand how C. gigantea respond to Cd stress, which is useful for evaluating the potential of C. gigantea in the remediation of Cd-contaminated soils.