In this paper, we explore the optimal combination of femtosecond laser drilling parameters for micro-hole processing on DD6 single-crystal high-temperature alloy and analyze the significance of parameter variations on the microstructure characteristics of the holes. The L25(56) orthogonal test was performed by controlling six parameters during femtosecond laser ring processing: Average power, Overlap rate, Defocus rate, Feed amount, Gas pressure, and End position. It is found that the entrance of the micro-holes has good roundness, while a large variation in diameter is observed. The exit of the holes exhibits poor roundness, and the diameter variation is intensified compared with the entrance, there are some with jagged edges. After the extreme difference analysis, it is concluded that the defocus has the most significant effect on the hole drilling by femtosecond laser ring processing for DD6 single crystal high-temperature alloy. The increase of laser average power leads to the decrease of hole taper, and the feed of 0.02 mm is beneficial for processing small taper through-hole. In addition, the outlet diameter of the holes increases with the increasing of gas pressure after the pressure is greater than 0.25 MPa, and the effect of the end is smaller and other regular conclusions. Through the integrated equilibrium method, the optimized combination of the femtosecond laser drilling parameters for 400 µm through-hole with minimum taper is as follows: power 7.84 W, overlap 99%, defocus + 0.4 mm, pressure 0.25 MPa, feed 0.02 mm and end + 0.2 mm.