Improvement of the effectiveness of heat exchanger is the demand of compact and efficient cooling devices. In that respect, a numerical study of fluid flow and heat transfer has been conducted with different arrangements of simple vortex generator (VG) in a rectangular microchannel Reynolds number (Re) in the range between 200 and 1100. The combined effect of spanwise and pitchwise distance of VG on heat transfer is investigated rigorously to observe the dependence of heat transfer on both. By processing the numerical predictions through gene expression programing and genetic algorithm optimization, the output variations in heat transfer, or Nusselt number, and friction factor with Re and locations of VGs in the channel are predicted in the form of explicit equations. The predicted monotonic increase of the outputs with Re shows heat transfer enhancement of 40–135% at the cost of increased pressure drop by 62–186.7% with respect to channels without VGs.