The Yellow River delta is one of the most active regions in the world, where wetlands play a significant role in balancing the regional eco-environment. However, in past decades, it has been subjected to severe disturbance by nature and by humans. Thus, it is critical to figure out what changes have occurred during this period and what could be done in this region now to protect the local wetland system. Therefore, in this study, we took Landsat satellite imagery from 9 years (1973, 1979, 1985, 1992, 1995, 2000, 2005, 2010, and 2013) as data sources to build wetland thematic databases using the method of visual interpretation. Based on these databases, a Surface Wetland and Construction State Index (SWCSI) was constructed to indicate the state of the land cover. These were combined with Yellow River runoff and sediment data, regional precipitation, local GDP, aquatic product output, and crude salt output. Then, the driving forces and corresponding spatial heterogeneity of wetland variations in the past 40 years in regions of the Yellow River delta were quantitatively analyzed at regional and pixel scales. From this research, we concluded that the area of wetland in the Yellow River Delta declined during the years 1973-2013, accompanied by large-scale conversion of natural wetlands to artificial wetlands and non-wetland. In the past 40 years, the area of natural wetlands decreased by 42.67% (annual reduction of 30.58 km²). In contrast, the area of artificial wetlands increased by 490.52% (annual increase of 24.47 km²). As a result, the total wetland area was reduced by 7.99% (annual reduction of 6.13 km²). The variations of wetland in the Yellow River delta showed high spatial heterogeneities. Wetlands in coastal regions experienced artificial enhancement or wetland degradation, while those in estuarine regions experienced wetland construction and development; however, there were no changes in the western and southwestern traditional farming districts. On the regional scale, GDP was the dominant driving force for wetland variation in the Yellow River Delta. In the past 40 years, intensifying human activities and decreasing Yellow River runoff and sediment made a number of important changes (decreases in natural wetlands, increase in artificial wetlands, and degradation of regional wetlands) more serious. In contrast, a large area of natural wetland was constructed and developed in the estuary of the Yellow River because of the continuous runoff and sediment supply, although there has been an overall decline in these factors during the past 40 years. Therefore, the Yellow River runoff and sediment still played an important role in the evolution of wetlands in the Yellow River Delta, but this role was not very significant because these influences were regionally limited. The influence of regional precipitation on wetland evolution was extremely limited. This was perhaps due to the severe dependence of the regional wetlands on runoff. At the pixel scale, the driving factors of evolution of the Yellow River delta wetlands showed obvious spatial heterogeneity. This was mainly due to the spatial heterogeneity of driving force factors themselves.