Radiometric calibration in-flight is one of critical techniques for information quantification of optical satellite sensor. A calibration approach based on gray-scale targets has been presented. It substitutes the measured ratio of diffusion to global irradiance and atmospheric optical depth to the assumption of aerosol scatter. And the method could isolate the DN signal created by the targets from the response produced by background radiance sources, which simplify the calibration process. It can break the time and locale conditions limit of radiometric sites and achieve high precision, high frequency and normalizable calibration application for high spatial resolution multi-spectral sensor with full dynamic range. The results show that the calibration approach′s uncertainty is less than 3.5%. And the difference of calibration coefficient is less than 5% compared with the reflectance-based method. Simultaneously, this approach can also satisfy the application to the complex environment.