In order to solve the problems such as high block rate, severe damage to the filling bodies and top pillars on both sides during the two-step mining process, and high ore impoverishment rate encountered during the mining by sublevel drilling and stage open stope with subsequent filling method in Sanguikou lead-zinc mine, optimization research was conducted on the original blasting parameters. Using a diameter of the blast hole of 76 mm and based on the analysis of rock drillability and blastability, through theoretical calculation, it is determined that the row spacing is 1.8 m and the hole bottom spacing is 2.1 m; alternatively, the row spacing is 1.9 m and the hole bottom spacing is 2.0 m. According to on-site industrial tests, compared with the stope using the original blasting parameters, the optimized blasting parameters reduced ore impoverishment rate by 19.8%, ore loss rate by 4.6%, the explosive consumption by 12.2%, and the block rate by 34.8%. The simulation analysis of the blasting effect before and after optimization of blasting parameters was conducted using LS-DYNA finite element software, and the simulation results showed that when using optimized blasting parameters for blasting, the ore block rate is lower, and the damage to the filling body on both sides, top pillar, and rock drilling roadway arch line is minimal.