Sapindus mukorossi seeds are commonly drilled and processed into Buddha beads and other craft products. To improve the machining qualities of the micro-drilling of S. mukorossi seeds, the effects of drilling parameters (feed rate, drilling speed, and drill diameter) on the drilling force, hole diameter and hole morphology were found. The mechanism behind these changes was further analyzed. The drilling parameters 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 were the main factors that influenced the drilling force, and the drilling speed played a leading role that influenced 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 hole 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 processing accuracies and qualities, and provides a theoretical basis for the improvement of related drilling processing equipment.