The Yellow River Basin (YRB) plays a very important role in China’s economic and social development and ecological security, so studying the spatiotemporal variation characteristics of net primary productivity (NPP) and its influencing factors is of great significance for protecting the stable development of its ecological environment. This article takes the YRB as the research area, based on Moderate Resolution Imaging Spectroradiometer (MODIS) data, climate data, terrain data, land data, social data, and the gravity recovery and climate experiment (GRACE) data. The spatiotemporal evolution characteristics of vegetation NPP in the YRB from 2000 to 2022 were explored using methods such as trend analysis, correlation analysis, and geographic detectors, and the correlation characteristics of NPP with meteorological factors, social factors, and total water storage (TWS) were evaluated. The results indicate that the NPP of vegetation in the YRB showed an increasing trend (4.989 gC·m−2·a−1) from 2000 to 2022, with the most significant changes occurring in the middle reaches of the YRB. The correlation coefficient indicates that temperature and accumulated temperature have a significant positive impact on the change of NPP, while TWS has a significant negative impact. In the study of the factors affecting vegetation NPP in the YRB, the most influential factors are soil type (0.48), precipitation (0.46), and temperature (0.32). The strong correlation between TWS and vegetation NPP in the YRB is about 39%, with a contribution rate of about 0.12, which is a factor that cannot be ignored in studying vegetation NPP changes in the YRB.