Zirconia (ZrO2) ceramics have been applied in medical and industrial fields due to their excellent properties. Surface micro-nano fabrication could bring their performance advantages into full play and also extend their application ranges, ZrO2 ceramic with different microstructures was investigated by green femtosecond laser mico-drilling. Combined with the influence of different microstructures on the physical properties of materials, the effects of laser machining parameters (viz. processing power and processing time) on the morphology, diameter and depth of the micro-holes were systematically studied. Results show that ZrO2 with smaller grain size, more uniform microstructure and lower thermal conductivity has higher processing efficiency under the same processing parameters. By comparing the change of the diameter and depth with the laser processing parameters, it is found that the difference of the material microstructure has more obvious effects along the axial direction of micro-hole relative to the radial direction.