Down-the-hole (DTH) hammer drilling with reverse circulation is a novel, mobile, high-speed drilling system suitable for the specific requirements of mine rescue. This technology can be applied to shorten the rescue time during mine accidents. The performance of reverse circulation (RC) drilling depends on the structural design of the drill bit. An orthogonal experimental design is executed to investigate the effect of the structural design parameters of the large-diameter drill bit for drilling rescue wells on the cutting carrying capacity and reverse circulation performance. This study employs computational fluid dynamics (CFD) software to solve the Navier−Stokes equation for three-dimensional steady flow and calculate the flow field around the drill bit to evaluate the RC efficiency. Six key geometric parameters were proven to have a direct influence on the RC performance, including the diameter of suction nozzles Dn, the length of nozzles L, the quantity of nozzles N, the diameter of the pilot hole Dg, the inclination angle of nozzles θs, and the deflection angle of nozzles θd. The CFD simulation experiments were implemented according to the orthogonal array L18(37) and were analyzed using the range, variance, and regression analysis. A mathematical model was developed for the RC efficiency to understand the effect of the factors. The results show that the diameter of suction nozzles Dn has an essential effect on the RC performance of the drill bit. An ideal combination is Dn = 20 mm, L = 50 mm, N = 3, Dg = 50 mm, and θs = 35°, θd = 10°, which was obtained through variance analysis and validated via CFD simulation for higher efficiency. To verify its real performance, a large-diameter RC drill bit with a diameter of 1.2 m was manufactured and tested in the field. The result demonstrated that the drill bit had excellent cutting transport and reverse circulation performance.