Ti6Al4V alloy is one of the typical difficult-to-machine materials and often results in rapid tool wear, leading to poor machining quality in aircraft assembling. Compared to conventional helical milling, the ultrasonic assistant helical milling (UAHM) process has indicated its superior performance; however, it is still a great challenge to improve the hole surface quality and accuracy. In addition, few studies have been conducted on the effect of different variables and cooling strategies on the hole-making performance in longitudinal-torsional ultrasonic assisted helical milling (LT-UAHM). This paper, for the first time, reports effects of machining variables on geometric precision and surface roughness in LT-UAHM of Ti6Al4V. In addition, the lubrication/cooling mechanism on the simultaneous application of LT-UAHM and MQL is theoretically analyzed. The design approach of Taguchi experiment was employed to study how major variables such as the cutting speed, tangential feed, axial feed, and the workpiece hardness influence the dimensional and geometrical tolerances and surface roughness. This paper also discussed the effect of three cooling strategies, i.e., dry condition, air coolant, and minimum quantity lubrication (MQL) in LT-UAHM. Theoretical analysis demonstrated that the MQL coolant can be nebulized into hyper-fine droplets owing to the resonant cavitation phenomenon. Combined with the penetrating action caused by the separate-cutting principles of LT-UAHM, the cooling and lubrication performance of MQL was further enhanced. As a result, LT-UAHM with MQL had the most positive effect on circularity, cylindricity, nominal diameter, and surface roughness, contributing to 34%, 32%, 39%, and 40%, respectively. The second important machining factor was the cutting speed, contributing to 31%, 29%, 36%, and 22%, respectively. The tangential feed and workpiece hardness have the negative effect on geometrical accuracy, respectively.