Gas-lift reverse circulation drilling technology is one of the typical “bottom-hole negative pressure” drilling technologies. This technology can significantly reduce wellbore circulation pressure loss, alleviate the bottom-hole pressure holding effect, and effectively lower the probability of lost circulation. The core theory underlying this technology is multiphase flow in the wellbore. Based on gas–liquid two-phase flow theory, this paper develops a method for calculating bottom-hole pressure during gas-lift reverse circulation. The effects of key operational parameters on bottom-hole pressure were analyzed. The results show that bottom-hole pressure decreases as gas injection rate increases and as the gas injection point deepens. Moreover, the deeper the gas injection point, the greater the pressure reduction. Compared with the results from gas-lift reverse circulation drilling design and monitoring software applied to a shale gas well in southern Sichuan, the two sets of data differ by approximately 3%. The proposed calculation method can predict bottom-hole pressure under gas-lift reverse circulation conditions, overcoming the low accuracy of empirical formulas traditionally used in such operations. This has significant implications for advancing gas-lift reverse circulation technology in oil and gas well drilling.