Abstract: The asynchrony between water flow and sediment transport during the flood season in the Three Gorges Reservoir Area is known to influence the sediment deposition distribution and sediment discharge operations in this region. The spatiotemporal evolution of the dominant controlling factors and the underlying mechanisms driving this asynchrony remain inadequately understood. Based on hydrological data measured from 2003 to 2020 at major stations in the Three Gorges Reservoir area, in this study, we employed Spearman correlation analysis, random forest modeling, and semi-theoretical semi-empirical derivation to investigate the mechanisms driving water–sediment asynchrony in the region. The results indicated that from the upstream Qingxichang station to the dam-front Miaohe station, the dominant influence of inflow asynchrony decreased, while the effects of hydrodynamic factors (e.g., peak discharge) and boundary conditions (e.g., forewater level) increased progressively along the reservoir. Following the impoundment of the cascade reservoirs in the lower Jinsha River, the effect of inflow asynchrony decreased in the upper and middle sections of the reservoir, and the influences of the forewater level and hydrodynamic conditions enhanced in the dam–proximal zone. Note that sediment peak concentration is not a direct driving factor but indirectly affects water–sediment asynchrony by influencing the completeness of sediment peak propagation. From a kinematic perspective, the longitudinal variation in water–sediment asynchrony is driven by a dual-core mechanism: the difference in the propagation velocities between the flood and sediment peaks and the persistent effect of inflow asynchrony. This study presents the empirical relationship for asynchrony duration based on this mechanism, while effectively reproducing the longitudinal patterns of water–sediment asynchrony (R² = 0.74 at Miaohe station) for conditions wherein the inflow sediment peak concentration exceeded 2 kg/m³, thereby validating the rationality of the dual-core driving mechanism. Overall, this study advances the understanding of water–sediment asynchrony and its underlying mechanisms within the context of large reservoirs; our findings provide a scientific basis for effectively implementing sediment flushing operations in the Three Gorges Reservoir.