In industries such as aerospace and automotive, drilling many holes is commonly required to assemble different structures where machined holes need to comply with tight geometric tolerances. Multi-spindle drilling using a poly-drill head is an industrial hole-making approach that allows drilling several holes simultaneously. Optimizing process parameters also improves machining processes. This work focuses on the optimization of drilling parameters and two drilling processes-namely, one-shot drilling and multi-hole drilling-using the Taguchi method. Analysis of variance and regression analysis was implemented to indicate the significance of drilling parameters and their impact on the measured responses i.e., surface roughness and hole size. From the Taguchi optimization, optimal drilling parameters were found to occur at a low cutting speed and feed rate using a poly-drill head. Furthermore, a fuzzy logic approach was employed to predict the surface roughness and hole size. It was found that the fuzzy measured values were in good agreement with the experimental values; therefore, the developed models can be effectively used to predict the surface roughness and hole size in multi-hole drilling. Moreover, confirmation tests were performed to validate that the Taguchi optimized levels and fuzzy developed models effectively represent the surface roughness and hole size.