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Abstract The Nankai Trough megasplay fault hosts diverse modes of fault slip, ranging from slow slip events to megathrust earthquakes, and is responsible for related phenomena such as tsunamis and submarine landslides. All types of slip events require some kind of frictional weakening process in order to nucleate and propagate. We tested fluid-saturated, powdered megasplay fault samples in a direct shear apparatus under effective normal stresses of 2–18 MPa to investigate their friction velocity- and slip-dependence. The experiments show that for short distances (1 mm) after a velocity step, there is an evolution from velocity weakening at low effective normal stress to velocity strengthening at high effective normal stresses. Over a longer distance (5 mm), large velocity weakening is observed over all tested effective normal stresses. In all experiments, slip weakening behavior occurred with relatively large weakening rates at low effective normal stresses and smaller weakening rates at higher effective normal stresses. Critical stiffnesses for slip instability were calculated for both the velocity and slip dependence of friction to determine their relative importance. At shallow depths, velocity weakening would be the main cause of frictional instability for both small and large slip perturbations, whereas at greater depth instability requires either slip weakening over small slip distances, or velocity weakening induced by larger slip. Regardless of the underlying mechanism, the observed slip instability at lower effective stresses increases the likelihood for fault slip events to travel to the seafloor which may cause submarine landslides and tsunamis. Graphical Abstract