Rapid, non-destructive detection of wheat Fusarium head blight (FHB) is an important tool for disease control. Red-edge (RE) is a prominent spectral feature for determining crop conditions with the potential to enhance the accuracy of monitoring FHB regionally. This study explored the potential of RE for FHB monitoring based on Sentinel-2 Multispectral Instrument (MSI) data. The novel red-edge head blight index (REHBI) was developed to detect FHB at a regional scale. Hyperspectral data at the canopy scale was integrated to simulate Sentinel-2 multispectral reflectance using the relative spectral response (RSR) function of the sensor. Then, many differential and ratio combinations of Sentinel-2 bands that were sensitive to FHB severity were selected. REHBI was established based on these basic vegetation indexes (VIs), and the model developed from REHBI performed best in monitoring FHB severity (R 2 = 0.82, RMSE = 10.1). Additionally, the infected canopies with disease index (DI) values between 10 and 50 were classified as slightly diseased canopies. Ordinary least square (OLS) was used to test the performance of REHBI and two conventional VIs, i.e., OSAVI and RDVI, in monitoring slightly diseased canopies; REHBI outperformed these alternatives (R 2 = 0.69, RMSE = 3.6). To approximate real agricultural conditions, Poisson noise was added to the simulated Sentinel-2 multispectral data and generalized performance of VIs was evaluated again; REHBI still had the highest R 2 and lowest RMSE values (0.74 and 12.6, respectively). Finally, to validate REHBI's ability to detect FHB infection in agricultural production, it was applied to monitoring FHB in the wheat planting areas of Changfeng and Dingyuan counties from Sentinel-2 imagery. Generally, REHBI performed better in disease monitoring than OSAVI and RDVI. The overall accuracy was up to 78.6%, and the kappa coefficient was 0.51. Experimental results demonstrate that REHBI can be used to monitor FHB. INDEX TERMS Red-edge, wheat fusarium head blight, Sentinel-2, spectral analysis, disease index.