To solve the problem of the filling bodies failure on both sides of the room caused by differential blasting of large diameter deep holes in underground mine, the stress field generated by differential blasting should be studied to determine a reasonable edge hole spacing and a delay time between the holes. According to the stress wave propagation and attenuation law, the front and rear detonation hole distance, delay time, and edge hole distance generated by complex stress field were determined. Furthermore, the superposition of the stress wave generated by the two-hole differential blasting in the blasted rock mass and the filling body was analyzed according to the wave theory. The stress field function analytical formula of the two-hole differential blasting was obtained. Meanwhile, the collapse range of the blasted rock mass and the failure range of the filled body under different side hole spacing conditions under the same hole spacing and delay time were determined. The LS-DYNA numerical simulation software established six numerical models, and the stress critical points were selected in the blasted rock mass and filling body for analysis after simulating the initiation of explosives under different schemes. The simulation results show that different edge hole distances had almost no effect on the collapse range of the exposed rock mass when the distance between edge holes was more significant than the range of the crack zone. Appropriately increasing the distance between edge holes can effectively reduce the damage caused by stress waves to the filling body. Finally, the field industrial test of four groups of blasting parameters was carried out, and the optimized blasting parameters were determined as the spacing between the two holes on the same side was 2.0 m, the delay time between the front and rear initiation holes was 9 ms, and the side hole spacing was 1.8 m.