DD5 Ni-based single-crystal superalloy has presented a wide application prospect in aerospace, marine, nuclear reactor, and chemical industries due to its excellent comprehensive performances caused by the crystal boundary as the crack source complete elimination. However, because of the low thermal conductivity and strong adhesion characteristic, DD5 is difficult to machine and the research on this field is still blank. Therefore, the purpose of this paper is to investigate the material machining mechanism and optimize the milling performance. Based on the DD5 metallographic structure characteristics, the directional cutting method was proposed firstly. Then, considering the wear characteristic and failure mode of the tools with different coating materials, the milling tool proper selection was executed. Moreover, combining with the molecular dynamics (MD) simulation, slot milling experiments, and slip system theory, the best milling path was confirmed. In addition, considering the machining environmental sustainability, the milling performances acquired under the dry, minimal quantity lubrication (MQL) and water-based MQL conditions were evaluated and compared. Finally, in order to optimize the machining parameter sequence quantitatively and ascertain the milling and cooling interactive effect mechanism, response surface method (RSM), back-propagation artificial neural network (BP-ANN), genetic algorithm (GA), and uniform design experiments were all adopted. With the anticipation to improve environmental sustainability and milling performance simultaneously, the milling experiments on the DD5 (001) crystal plane along the [110] crystal direction under the water-based MQL technology with PVD-TiAlN-coated tools were conducted and the parameters of main spindle linear speed v c = 20 m/min, tool feed per tooth f = 8.97 μm, oil flow rate Q = 68.21 ml/h, the ratio of water and oil R = 0.94 and the air pressure P = 1.79 bar were used. Then, the better surface roughness Sa = 2.05 μm and the lower milling force F = 14.38 N can be acquired simultaneously based on the verification of the uniform design experiment results.