Ecological security is of central significance for maintaining the integrity and stability of regional ecosystems. Nevertheless, current academic research systematically studying the complex driving mechanisms behind ecological security is deficient. Therefore, this study utilised ecological sources (ESs) and ecological resistance surfaces (ERSs) to calculate and obtain the Ecological Suitability Index (ESI), thereby reflecting the ecological security status. The drivers of ESI in different areas of the Yellow River Basin (YRB) from 1990 to 2020 were explored using the random forest (RF) model and GeoDetector. The results of the study show that: (1) according to the results of the RF model, LANDUSE, NDVI, and PRE are the most important driving factors of the ESI in the upper (UYR), middle (MYR), and lower (LYR) reaches of the YRB; (2) according to the results of GeoDetector factor detection, in the UYR and MYR, the ESI is primarily influenced by natural factors such as NDVI and PRE, showing particularly significant impacts in 2010 and 2020; (3) in the LYR, the ESI is mainly influenced by NDVI, but the degree of influence from socioeconomic factors has significantly strengthened. This study provides a decision-making direction for ecological protection and coordinated development in the YRB.