The widespread use of de-oiling hydrocyclones to separate oil and water from wastewater has attracted the interest of many researchers. The close density of oil and water, and their breakup and coalescence, make research in this area quite challenging. In the present research, a numerical Eulerian-Lagrangian (E-L) framework was developed to investigate the effects of droplet interaction, inlet size distribution, and phase-coupling schemes on hydrocyclone efficiency. The results show that droplet interaction, including the breakup and coalescence phenomena and the inlet size distribution, should be considered to obtain accurate numerical results in the E-L framework. Using the E-L approach, the efficiency of de-oiling hydrocyclones was estimated with a minimum error of 7%. Also, the phase-coupling schemes affected the velocity field of the continuous phase (water) and the separation efficiency. The coalescence and breakup-dominated regions were investigated in different designs of de-oiling hydrocyclone using the E-L approach. Examining different designs shows that large changes in cone angle create a region of high turbulence and enhance droplet breakup. It can be concluded that the Sauter mean diameter of droplets and, consequently, the separation efficiency decrease in designs with the sharp cone angle.