Based on the research on the changes of climate, disasters, vegetation, and land use in the past 40 years, this study made a comprehensive assessment of the characteristics of changes of temperature, dry/wet conditions, and extreme droughts and floods, and the general trend of land cover caused by the agricultural land use, in the middle and lower reaches of the Yellow River over the past two millennia. We also discussed the general relationships between the above changes and the sedimentation, breaches, and avulsions in the lower Yellow River from a historical perspective. The main conclusions are as follows. (1) During the past two millennia, multi-scale periodic fluctuations of temperature and dry/wet conditions were significant in the middle and lower reaches of the Yellow River, but the dry/wet changes in the middle and the lower reaches were not completely synchronized. Frequencies of extreme droughts and floods varied in different time periods. (2) As early as in the late Western Han Dynasty, the middle and lower reaches of the Yellow River had already been developed into an agricultural area with a spatial range similar to today’s, where, especially on relative flat terrains, only limited natural vegetation remained. Since then, the intensity of reclamation showed an increasing trend in general, although it fluctuated greatly over time. (3) The changes of climate and land cover had influenced the water-sediment balance, channel sedimentation, and riverbed stability in the middle and lower reaches of the Yellow River, and driven, as an important trigger, the repeated diking-sedimentation-suspended river-burst and avulsion cycle in the lower Yellow River during the historical period. These understandings can provide historical backgrounds for further revealing the characteristics of environmental change in the middle and lower reaches of the Yellow River and their impacts on the security of the lower Yellow River region.