Via-hole processing was carried out in the 2 mm thick nickel-base superalloy GH4037 by the millisecond pulse laser precision drilling system. In order to solve the problem that the overflow of the set number of via-hole machining laser pulses in the traditional control variable method might cause many adverse effects, the mathematical model of the threshold number of laser pulses was established by the penetration detection technology. The influence of the defocusing amount, the beam expanding ratio and the pulse repetition frequency of the laser on the inlet and outlet aperture, the taper and the drilling efficiency was studied by the improved control variable method based on the mathematical model. The results indicated that when the defocusing amount was -2 mm to 0 mm, the beam expanding ratio was 2 to 4, the repetition frequency was 45 Hz to 85 Hz, and the auxiliary gas was oxygen, the drilling efficiency could be improved by 89.09% compared with the traditional control variable method.