Three-dimensional (3D) natural convection with isothermal discrete heat sources in a cubical cavity has been carefully studied using the 3D vector potential–vorticity formulation. Based on the finite volume method, the governing equations are solved with a homemade computational code (written in Fortran). Assuming that all cavity vertical walls are adiabatic, the upper wall of the cavity is kept at a cold temperature. However, in the bottom face, heat sources are placed under different configurations. The size of the discrete sources, their positions, and their numbers are varied for different Rayleigh numbers. The Prandtl number is fixed at 0.71. Three-dimensional distribution of the temperature iso-surfaces, the heat transfer rate, and entropy generation is evaluated. It is found that heat transfer and entropy generation are strongly affected by the arrangement of the discrete heated sources. In conclusion, the heat transfer rate is maximized, and the entropy generation is minimized for the inline arrangement of more than two heaters compared to the diagonal one.