A regional numerical simulation and observations were used to investigate the various processes controlling mixed-layer salinity balance on seasonal and interannual time scales in the Gulf of Guinea. Processes were quantified using a mixed-layer salt budget. Model results correctly reproduced the mean, phase, and amplitude of observed seasonal near-surface salinity. The results indicated that on seasonal time scales, the mixed-layer salinity balance differed from one region to another. The surface salinity seasonal cycle was characterized by strong salinization during May for coastal areas north and south of the equator. Model results suggested that vertical mixing controls the mixed-layer salinity increase at the equator during May, while both vertical mixing and vertical advection contribute to the salinity increase in coastal regions. We also determined that freshening from horizontal advection and freshwater flux tended to balance the salinization effects of vertical diffusion and vertical advection during the seasonal cycle. On interannual time scales, based on the mixed-layer salinity balance and sensitivity experiments, we determined that for the northern and equatorial Gulf of Guinea, changes in near-surface salinity were largely due to changes in precipitation and winds. For the southern Gulf of Guinea, only wind changes were determined to be important for explaining near-surface salinity changes.