Molecular dynamics simulations are used to investigate the frictional interactions between a rough surface and a macromolecule moving under the action of an external drag force. By increasing the driving force, three different frictional regimes are identified: stick–slip, slip, and Stokes-dominated dynamics. In the slip regime, the behavior of the friction force is found to be well described by an explicit formula, which resembles the classical Amontons–Coulomb friction law. The motion of the molecule is governed by a kinetic frictional contribution resulting from the complex polymer–substrate energetic landscape of chain-substrate interactions. The friction response can be rationalized in terms of the laterally averaged normal and tangential forces arising from this interaction potential. The results shed light on the mechanics of friction between interacting systems at the nanoscale.