Summary In the completion of oil and gas wells, successful cementing operations essentially require the complete removal of the drilling mud and its substitution by the cement slurry. Therefore, the displacement of one fluid by another one is a crucial task that should be designed and optimized properly to guarantee the zonal isolation and integrity of the cement sheath. Proper cementing jobs ensure safety, whereas poor displacements lead to multiple problems, including environmental aspects such as the contamination of freshwater-bearing zones. There are a number of factors, such as physical properties of fluids, geometrical specifications of the annulus, flow regime, and flow rate, that can remarkably affect the displacement efficiency. The shape of the interface plays an influential role during the displacement process. For a highly efficient displacement, the interface has to be as flat and stable as possible. However, unstable and elongated interfaces are associated with channeling phenomena, excessive mixing, cement contamination, and, consequently, unsuccessful cementing operations. Thus, the stability of the interface between the two fluids has major importance in cementing applications. In the present work, a novel method for the prediction of interface instability and displacement efficiency is introduced. Instability analyses of the interface between the two fluids are carried out following the main ideas of the original Rayleigh-Taylor (RT) and Kelvin-Helmholtz (KH) instabilities. Moreover, with the same analyses, optimized designs for the improvement of the displacement process in any specific situation can be proposed. The influence of density, rheological properties, surface tension, and flow rate of the fluids on the instability and shape of the interface, and consequently on the displacement efficiency, is studied. The 3D-computational-fluid-dynamics (CFD) simulations are performed with commercially available CFD software to study several displacement cases. To validate the results, numerous experiments were conducted for fluids with various combinations of physical properties and operational conditions. For one of the inefficient displacement cases, an optimized design is provided on the basis of a study of the instability of the interface, and the improvements are validated by CFD simulations. The results present the effect of fluid properties, geometrical configurations, and flow rate on the instability of the interface and displacement efficiency. A reasonably good agreement between the results of all approaches presented in the paper is observed, and they all emphasize the importance of the proper selection of fluid properties and flow rates for any specific sequence—to minimize the degree of contamination and mixing. The discussions and results of this work provide insight into the displacement process, beneficial guidelines for industrial applications, and compelling evidence of the importance of correct predictions and appropriate designs of the displacement of fluids in cementing operations.