Instability and mixing are ubiquitous processes in river plumes but their small spatial and temporal scales often limit their observation and analysis. We investigate flow instability and mixing processes in the Gironde river plume (Bay of Biscay, North-East Atlantic ocean) in response to air-sea fluxes, tidal currents, and winds. High-resolution numerical simulations are conducted in March (average river discharge) and in August (low discharge) to explore such processes. Two areas of the Gironde river plume (the bulge and the coastal current) experience different instabilities: barotropic, baroclinic, symmetric, and/or vertical shear instabilities. Energy conversion terms reveal the coexistence of barotropic and baroclinic instabilities in the bulge and in the coastal current during both months. These instabilities are intensified over the whole domain in August and over the inner-shelf in March. The Hoskins criterion indicates that symmetric instability exists in most parts of the plume during both periods. The evolution of the Gironde plume with the summer stratification, tidal currents and winds favors its development. During both seasons, ageostrophic flow and large Rossby numbers characterize rapidly-growing and small-scale frontal baroclinic and symmetric instabilities. The transition between these instabilities is investigated with an EKE decomposition on the modes of instability. In the frontal region of the plume, during both months, symmetric instabilities grow first followed by baroclinic and mixed ones, during wind bursts and/or high discharge events. In contrast, when the wind is weak or relaxing, baroclinic instabilities grow first followed by symmetric and then mixed ones. Their growth periods range from a few hours to a few days. Mixing at the ocean surface is analyzed via Potential Vorticity (PV) fluxes. The net injection of PV at the ocean surface occurs at submesoscale buoyant fronts of the Gironde plume during both months. Vertical mixing at these fronts has similar magnitude as the wind-driven and surface buoyancy fluxes. During both months, the frontal region of the plume is restratified during wind relaxation events and/or high river discharge events through frontogenetic processes. Conversely, wind bursts destratify the frontal plume interior through non-conservative PV fluxes.