During orthopedic surgery, drilling operations require minimum drilling damage to bone and rapid recovery after surgery. A cortical bone drilling model was established based on ABAQUS, and the effects of feed speed, spindle speed and drill diameter on axial force were studied through a central composite experimental design.Multivariate linear regression analysis of the experimental data was done using MATLAB, the mathematical model of drilling force was gotten. Combined with the genetic algorithm in MATLAB, the best combination of drilling parameters (feed speed and spindle speed) and drill diameter was found for the minimum axial force during drilling of the bones. It provides theoretical guidance for analyzing the distribution of drilling force during bone drilling operation and provides a reference for selection of drilling dosage for bone drilling by orthopedic surgeons.