A two-dimensional numerical model has been developed to investigate the mixed convection heat transfer and entropy generation of Al2O3-water nanofluid inside a rough cavity. The numerical model is developed using commercial finite volume software ANSYS-FLUENT inside a square cavity with various roughness elements. Here the vertical walls of the cavity are adiabatic, horizontal walls are maintained at constant temperatures, and the top wall is moving at a constant velocity. The rough bottom wall is maintained at a higher temperature, where the roughness elements are introduced by making the surface wavy. The effects of elements number and amplitude of the roughness elements on the heat transfer, fluid flow, and entropy generation are analyzed. The flow fields, temperature fields, and heat transfer rates are examined for different values of Reynolds numbers, while the entropy generation is characterized by the Bejan number, heat transfer irreversibility, and fluid friction irreversibility. The outcome of this study provides some important insight into the heat transfer behavior due to the surface roughness, which could potentially be used in developing novel geometries with enhanced and controlled heat transfer for complex engineering applications.