Centrifugal compressors are mainly designed with the best efficiency point in mind and the focus oriented toward the impeller. The vaned diffuser geometry is usually developed using simple shapes, such as prismatic blades or wedges, which are unable to account for the flow distortion at the impeller outlet. Investigations of diffuser modifications using computational fluid dynamics (CFD) during the design phase can help to extend the operating range. In order to assess the effect of such modifications, simulations in off-design conditions need to be performed. Accurate predictions of local flow structures at such conditions require a robust flow solver with mixing-plane interfaces and advanced turbulence modeling capabilities. In recent years diffuser modifications were performed mainly based on manual trial-and-error approaches and show considerable potential for improvements. To accelerate the process and allow automation, which is crucial in industrial applications, it is suggested to use an adjoint-based optimization algorithm for diffuser shape design. In this work, a discrete adjoint solver implemented into a robust pressure-based CFD framework was used. While many optimization studies follow the frozen-turbulence approach, which essentially ignores the dependency of the sensitivity on the turbulence quantities, the present adjoint solver fully includes such effects. Automatic differentiation even allows for flexibility with respect to the choice of turbulence model. Any model available in the primal solver can also be used in the adjoint solver. In this particular case, the k–ɛ enhanced wall treatment model was used, since it shows good convergence behavior and is capable of predicting the machine characteristic even at off-design conditions. Mesh morphing was realized via the free-form deformation method, which provides stable mesh deformation and offers a simple and fast setup procedure. Several optimizations were conducted for the RWTH Aachen “Radiver” centrifugal compressor case with vaned diffuser. It was shown that an optimization strategy using a multi-operating point approach, considering part- and overload conditions, is capable of improving the peak efficiency as well as the overall shape of the machine characteristic.