The turbulent separated flow through an asymmetric diffuser with and without manipulation of incoming turbulence-driven mean secondary vortices (MSVs) from a rectangular duct is investigated by large-eddy simulations. The simulations carried out for two diffuser geometries reveal that by introducing a small amount of meanflow kinetic energy via the MSVs into the flow, the complex three-dimensional separation behaviour and pressure recovery can be effectively controlled. Manipulated MSVs were found to enhance cross-sectional transport of high-momentum fluid, which determined the location, shape, and size of the separation bubble. The integral effect was a delay or expedition in the onset of separation. This change strongly affected the conversion of mean-flow kinetic energy to pressure, in particular for the front part of the diffuser. In addition, a substantial reduction in total pressure loss could be achieved. The manipulation of the MSVs is an efficient mechanism for performance enhancement in the cases investigated. The results have important implications for both control and statistical modelling of turbulent separated flow in rectangular diffusers.