Droplet-based microfluidics is a widely used technology in various chemical and biological applications. Droplet formation is an essential part of droplet-based microfluidics. This work applied and summarized a combination of techniques for speeding up computational fluid dynamics (CFD) simulations based on the Volume of Fluid method for the droplet generation process. To demonstrate the efficiency of the applied techniques, numerical modeling and simulation of droplet formation in a cross-shaped square microchannel were carried out. Water-butanol and water-toluene two-phase systems were considered under various flow rate conditions. Flow visualization experiments were conducted to validate the numerical results. In addition, a parametric analysis on the influence of viscosity, interfacial tension, and three-phase contact angle on the droplet formation was carried out to demonstrate the performance of the numerical setup. The simulated fluid flow dynamics showed good agreement with the experimental data. The CFD model was also verified by simulating the droplet formation in a T-shaped rectangular microchannel. The presented setup shows promising potential for development of chips for droplet generation by testing virtual prototypes. Due to the possibility to model the droplet formation process at an acceptable computational cost, time savings in the research and design cycles can be significant. (C) 2020 The Author(s). Published by Elsevier B.V. on behalf of Institution of Chemical Engineers.