[Objective] The spatial and temporal characteristics of human disturbance in the Guangdong-Hongkong-Macao Greater Bay Area (GHMGBA) was determined in order to provide reference data for solving a series of human-land relationship problems and sustainable development caused by rapid regional economic development. [Methods] The temporal and spatial characteristics of hemeroby from 1980 to 2018 were analyzed, and the spatial heterogeneity of hemeroby from natural and social driving factors was analyzed by using GeoDetector. [Results] ① Land use in the GHMGBA was classified mainly as forest land and cultivated land, but urban land and other construction land had increased by 4.25 times in the past 40 years. ② During the past 40 years, the GHMGBA was dominated by moderate hemeroby, but had developed towards severe and complete. The total intensity of hemeroby was higher in more developed cities and lower in under developed cities. The stability of hemeroby was generally highly stable, but the unstable area expanded rapidly during 2010—2018. ③ The spatial distribution of the total intensity of hemeroby was mainly affected by night light index, traffic density, annual average temperature, elevation, and slope. The factor interaction was mainly manifested as two-factor enhancement and nonlinear enhancement. The total intensity of hemeroby in core cities in the GHMGBA was mainly driven by socio-economic factors, and the total intensity of hemeroby in peripheral cities was mainly driven by natural environmental factors. [Conclusion] The hemeroby of the GHMGBA is expanding and increasing. Under the constraints of topography and geomorphology, the intensity of human activities drives the degree of hemeroby to expand with the city as the center and the sub-center.