In natural farmland ecosystems, cadmium (Cd) pollution in rice has attracted increasing attention because of its high toxicity, relative mobility, and high water solubility. This study aims to develop a spectral index for detecting Cd stress in rice on a regional scale. Three experimental sites are selected in Zhuzhou City, Hunan Province. The hyperspectral data, chlorophyll (Chl) content, leaf area index, average leaf angle, Cd concentration in soil, and Sentinel-2A images from 2017 and 2018 are collected. A new spectral index sensitive to Cd stress in rice is established based on the global sensitivity analysis of the radiative transfer model PROSPECT + SAIL (commonly called PROSAIL) model with the auxiliary of the field-measured data. The heavy metal Cd stress-sensitive spectral index (HCSI) is devised as an indicator of the degree of Cd stress in rice. Results indicate that (1) the HCSI developed based on Chl is a good indicator of rice damage caused by Cd stress, that is, low values of HCSI occur in rice subject to relatively high pollution; (2) compared with common spectral indices, such as red-edge position and red-edge Chl index, HCSI is more sensitive to Chl content with higher Pearson correlation coefficients with respect to Chl content, ranging from 0.85 to 0.95; (3) HCSI is successfully applied in Sentinel-2A images from the two different years of monitoring rice Cd stress on a regional scale. Cd stress levels in rice stabilized, and the largest area percentage of each pollution levels of Cd decreased in the following order: No pollution (i.e., 40%), low pollution (i.e., 35%), and high pollution (i.e., 25%). This study indicates that a combination of simulation data from the PROSAIL model and measured data appears to be a promising method for establishing a sensitivity spectral index to heavy metal stress, which can accurately detect regional Cd stress in crops.