Wetlands are sensitive to hydrological conditions and human influence. The Abras de Mantequilla wetland (AdM) located at the centre of the Guayas River Basin (Western Ecuador), was declared a Ramsar site (2000) due to its important role in the conservation of bird fauna diversity. The wetland also supports significant populations of fish, including endemic species. The area exhibits two seasons: (i) a wet season (January–May); and (ii) a dry season (June–December). For the area of interest data is scarce, and a hydrodynamic model did not exist. In order to evaluate the interannual hydrodynamics and inundation patterns variability of this wetland system, a 2D hydrodynamic model was developed using the Delft3D software suite. Local knowledge was combined with field observations and expert elicitation to construct an appropriate model for the area. Results show that the Abras de Mantequilla is a river-wetland system that experiences extreme variations in hydrodynamic conditions from low water depths and almost stagnant conditions during the dry season, to a very dynamic behaviour during the rainy season. The inundation area ranges between 5 to 27 km2, water depths vary from 0.4 to 9 m and flow velocities from 0.0 up to 0.9 m/s. The “Nuevo River” is the main inflow to the wetland, with an overall contribution of about 85–90%, with peak discharges during February and March. A numerical tracer analysis indicated that the wetland can be divided into three main areas (upper, middle and low), with higher residence times found in the middle area. Overall, based on numerical hydrodynamic simulations it was possible to obtain adequate indications of the relative importance of the different river inflow conditions, as well as spatial and temporal inundation patterns, velocities and residence times under hydrological conditions varying from dry to extremely wet years. Furthermore, the hydrodynamic model provides a basis for other studies such as water quality assessment and primary production dynamics, as well as for determining the habitat suitability for fish.