<p>Nickel-based alloys, owing to their superior performance characteristics, find extensive application in turbine and aero-engine blade manufacturing. The precision machining of micro-scale apertures in these materials necessitates the use of micro flat-end drills along with precise positioning and structural joints between miniature components. Notably, Waspaloy—a representative nickel-based superalloy—exhibits exceptional machinability challenges characterized by high toughness, elevated hardness, and outstanding corrosion resistance. Through an integrated approach combining theoretical analysis, computational simulation, and experimental validation, this investigation systematically evaluates the effects of cutting parameters on critical performance metrics including axial cutting forces, tool wear progression, bore geometry integrity, bore wall surface roughness (Ra), and chip formation mechanisms. The experimental design incorporates both single-variable testing and response surface methodology (RSM) to enhance the reliability of machining condition optimization for micro-drill/workpiece interactions in flat-bottomed micro-hole processing. Experimental results demonstrate that under dry cutting conditions with optimized parameters (feed rate <i>v</i>_<i>f</i> = 2 mm/min and spindle speed <i>n</i> = 16,000 rpm), the axial force is smaller, the service life of micro-drill is longer, and the machining micro-hole accuracy is higher.</p>