In the present work second-order Stokes theory has been extended to the case of a generally shaped bottom profile connecting two half-strips of constant (but possibly different) depths, initiating a method for generalizing the Stokes hierarchy of second- and higher-order wave theory, without the assumption of spatial periodicity. In modelling the wave–bottom interaction three partial problems arise: the first order, the unsteady second order and the steady second order. The three problems are solved by using appropriate extensions of the consistent coupled-mode theory developed by the present authors for the linearized problem. Apart from the Stokes small-amplitude expansibility assumption, no additional asymptotic assumptions have been introduced. Thus, bottom slope and curvature may be arbitrary, provided that the resulting wave dynamics is Stokes-compatible. Accordingly, the present theory can be used for the study of various wave phenomena (propagation, reflection, diffraction) arising from the interaction of weakly nonlinear waves with a general bottom topography, in intermediate water depth. An interesting phenomenon, that is also very naturally resolved, is the net mass flux induced by the depth variation, which is consistently calculated by means of the steady second-order potential. The present method has been validated against experimental results and fully nonlinear numerical solutions. It has been found that it correctly predicts the second-order harmonic generation, the amplitude nonlinearity, and the amplitude variation due to non-resonant first-and-second harmonic interaction, up to the point where the energy transfer to the third and higher harmonics can no longer be neglected. Under the restriction of weak nonlinearity, the present model can be extended to treat obliquely incident waves and the resulting second-order refraction patterns, and to study bichromatic and/or bidirectional wave–wave interactions, with application to the transformation of second-order random seas in variable bathymetry regions.