Manufacturing companies are focusing on continuous process development to thrive in today’s quality-conscious market. It is particularly relevant to investigate machining processes for advanced materials such as superalloys. Drilling is a major operation that is used in the majority of manufacturing processes. Hence, this research work is focused on investigating the drilling performance of the Monel K500. The output responses under consideration are metal removal rate (MRR), surface roughness, and tool wear. Various contemporary techniques were utilized in this work, namely machine learning methods, artificial neural networks, principal component analysis, and grey relation analysis using uncoated, coated, and HSS (high-speed steel) drills. After annealing, the softened material can be easily machined to increase the MRR and decrease tool wear and surface roughness. The experimental results show that, after annealing, the surface roughness values for HSS drills have been reduced by 23.86%, uncoated drills by 27.29%, and coated drills by 29.27%, respectively. Moreover, tool wear values for HSS drills decreased by 28.51%, uncoated drills by 34.7%, and coated drills by 33.71%, based on the relative error approach. MRR values for HSS drills increased by 20.51 %, uncoated drills by 23.08%, and coated drills by 23.5%, respectively. For PCA (principal component analysis), feed (47%), and for GRA (gray relation analysis), feed (40.1%) will be the significant parameter followed by speed, and both methods have identified the same experimental run values for optimization of cutting parameters. The theoretical values were predicted using machine learning methods, which utilized the Python language using the Google Colab and then validated with experimental values. The predicted values obtained by the decision tree are close to the measured values as compared to support vector regression and K-nearest neighbor based on relative error. The estimated values obtained by the ANN (artificial neural networks) approach, using Easy NN plus software, match well with the actual values, with a slight deviation.