Drilling of micro-cooling holes in turbine blades on hard material like Inconel 625 is one of the noteworthy applications of micro-drilling. An experimental investigation on the hole quality assessment and drill bit tool life while micro-drilling of Inconel 625 is not explored in detail. This paper presents the experimental study and multi-response optimization of test parameters of Inconel 625 in micro-drilling conditions using desirability approach. Test parameters are micro-drill diameter, spindle speed, and feed rate. The micro-drilling test, based on the Taguchi L27 design, is performed on a 2-mm plate thickness of Inconel 625 with uncoated micro-drill. After each drilling test, the hole properties including hole diameter, circularity error, overcut, taper ratio, cylindricity and hole damage factor are measured, and the results are examined. In addition to that, the number of micro-holes that can be drilled is analysed to observe the lifelong tool performance on hole quality assessment. As a result, the number of holes drilled before tool breakage is 25 in magnitude. The deviation in hole diameter, cylindricity, circularity error, roundness, overcut, taper ratio, and hole damage factor obtained is increased to 5.5%, 87.2%, 50.5%, 5.7%, 77.4%, 20% and 5.4% from 1st hole to 25th hole at an optimal level of high tool diameter, low speed, and high feed rate. The most significant drilling parameters for the above-studied response factor are tool diameter and spindle speed. From the results, the 0.8 mm is the most suitable tool diameter for hole quality achievements and productivity in practical micro-drilling applications. © 2020, King Fahd University of Petroleum & Minerals.