This paper discusses development and validation of a 3-D, non-hydrostatic, Reynolds-Averaged Navier–Stokes (RANS) model using the Volume of Fluid (VOF) approach to simulate flooding events in natural environments. A series of validation simulations in simple and complex geometries are performed to test the different modules of the flow solver. The paper also discusses the differences between simulation results obtained using the 3-D model and those obtained using a standard, 2-D hydrostatic, depth-averaged model. The predictions by the two models show fairly large differences in regions where 3-D effects are expected to be significant (e.g., in regions containing highly-curved river reaches and near hydraulic structures). Then, the validated 3-D model is employed to investigate the efficiency of using flood-protection walls to reduce adverse effects of flooding in the Iowa River near Iowa City, Iowa, USA. Finally, the propagation of a flood wave in a reach of the Iowa River containing a bridge is simulated and the effects of the flow becoming pressurized beneath the bridge deck are discussed. For such applications, in which the regime can change locally between open channel and pressurized flow, the use of fully 3-D, non-hydrostatic models may be the only viable option to accurately predict flow hydrodynamics and its effects on bed shear stresses and sediment entrainment potential, especially around locations where the flow becomes pressurized.