In bone fixation, frictional heat effect in orthopedic surgery has a potentially hazardous for soft tissues. Saline water irrigation has frequently been practiced preventing the thermal damage and limiting the applied cutting forces in high-speed orthopedic drilling. The application of excessive cutting fluids limits the heat and applied forces; however, it isn’t an environmentally friendly solution. In this work, a novel micro-irrigation system was developed to provide a mixture of air and saline water, having a small quantity of cooling spray (SQCS) at higher pressure into the cutting zone. This SQCS limits the frictional heat and providing lubrication and near to dry clean operative zone through a superior cooling effect compared to conventional irrigation. The carbide drills were used to make a hole in the fresh calf tibia bone. In addition, response surface methodology (RSM) was used to design the experiments. The regression models were developed between the input design parameters and performance measures to explore the relation under proposed micro-irrigation and facilitate the multi-objective optimization. Besides, cost analysis for the process has been performed. Thus, this work offers an integrated analysis to purely study and understand the bone drilling process under employing micro-cooling spray.