The Magdalena River (Bocas de Ceniza) forms a microtidal estuary subjected to numerous interventions aimed to guarantee navigability towards the port of Barranquilla, Colombia. Significant sedimentation processes are still frequent in this area, however. Understanding the dynamics of both saltwater intrusion and mixing conditions is a fundamental requisite to understanding the sedimentation dynamics in these types of estuaries. The effects of river discharge, tide, and winds on stratification patterns, and mixing and saltwater intrusion dynamics in the estuary of the Magdalena River were evaluated, focusing on the effects of river discharge variability. The three-dimensional hydrodynamic model MOHID was implemented, and calibration and validation of the model were carried out using in situ velocity, temperature, and salinity data, obtaining Skill values greater than 0.90. To cover a wide range of variability in the main forcing factors (fluvial discharge, tide, and wind), the conditions recorded in 2010 were simulated when both phases of the El Niño–Southern Oscillation phenomenon occurred. During that year, the river discharge ranged between 2465 and 16,463 m3 s 1. Results revealed a stratified, saltwater wedge estuary, the dynamics of which were mainly dominated by river discharge. Tide and winds altered saltwater intrusion dynamics, mainly during low-discharge periods.