Bone grinding is an essential and vital procedure in most surgical operations. Currently, the insufficient cooling capacity of dry grinding, poor visibility of drip irrigation surgery area, and large grinding force leading to high grinding temperature are the technical bottlenecks of micro-grinding. A new micro-grinding process called ultrasonic vibration-assisted nanoparticle jet mist cooling (U-NJMC) is innovatively proposed to solve the technical problem. It combines the advantages of ultrasonic vibration (UV) and nanoparticle jet mist cooling (NJMC). Notwithstanding, the combined effect of multi parameter collaborative of U-NJMC on cooling has not been investigated. The grinding force, friction coefficient, specific grinding energy, and grinding temperature under dry, drip irrigation, UV, minimum quantity lubrication (MQL), NJMC, and U-NJMC micro-grinding were compared and analyzed. Results showed that the minimum normal grinding force and tangential grinding force of U-NJMC micro-grinding were 1.39 and 0.32 N, which were 75.1% and 82.9% less than those in dry grinding, respectively. The minimum friction coefficient and specific grinding energy were achieved using U-NJMC. Compared with dry, drip, UV, MQL, and NJMC grinding, the friction coefficient of U-NJMC was decreased by 31.3%, 17.0%, 19.0%, 9.8%, and 12.5%, respectively, and the specific grinding energy was decreased by 83.0%, 72.7%, 77.8%, 52.3%, and 64.7%, respectively. Compared with UV or NJMC alone, the grinding temperature of U-NJMC was decreased by 33.5% and 10.0%, respectively. These results showed that U-NJMC provides a novel approach for clinical surgical micro-grinding of biological bone.