Sapindus mukorossi seeds are commonly drilled and processed into strings and other craft products. To improve the machining qualities of micro-drilling of S. mukorossi seeds, the effects of these drilling parameters on the drilling force and pore morphology were found. The mechanism behind these changes was further analyzed. The drilling parameters (feed rate, drilling speed, and drill diameter) and machining process for the micro-drilling of S. mukorossi seeds were optimized. Results indicated that each drilling parameter influenced the drilling force and hole-machining quality by affecting the amount of cutting, the working conditions of the drill bit, chip formation, and the generation of drilling heat. Moreover, the feed rate and drill diameter are main influence factors that influence the drilling force, and the drilling speed plays a leading role that influences the hole-machining quality. Interestingly, for the drilling of S. mukorossi seeds, a feed rate of 0.03 mm/r, a drilling speed of 6 m/min, and a drill-bit diameter of 0.9- or 1.5 mm resulted in a hole with high accuracy, good pore morphology, and minimal wear on the drill bit. This study facilitates the selection of suitable drilling parameters and processing technology for the micro-drilling of S. mukorossi seeds to improve the processing accuracies and qualities, and provides a theoretical basis for the improvement of related drilling processing equipment.