Slip during large earthquakes occurs along faults that are hundreds of kilometers long (eg, San Andreas fault, Alpine fault), yet, the dynamic weakening that drives these earthquakes is controlled by nano-to micro-scale frictional processes (eg, flash heating (Rice, 2006), gouge lubrication (Reches and Lockner, 2010), asperity deformation (Dieterich and Kilgore, 1994)). We analyzed these processes along experimental faults that slipped at rates approaching seismic velocity and which displayed intense dynamic weakening of 50%–70%. Sheared fault surfaces were extracted, and then Atomic Force Microscopy (AFM) was used to (1) measure friction on sub-micron scale, and (2) determine the three-dimensional morphology at the nanoto micro-scale. The sheared surfaces developed a prevalent anisotropy with a weaker and smoother axis along the slip direction. The nanoscale friction coefficient correlates well with sheared surface roughness: the friction coefficients dropped only on surfaces with RMS values of< 100 nm while rougher surfaces showed no weakening. Our analysis indicates that slip-smoothing at high slip-velocities can be an effective mechanism of dynamic weakening.