Propylene oxide (PO) is widely used in fuel–air explosive (FAE) and pulse detonation engines (PDE). The explosion process of PO/air mixture in a 20 L spherical container under high-temperature source ignition was studied through experiment and numerical simulation. A good agreement was observed between the experimental and simulation results. The ignition temperature (1100–2500 K) and initial droplet size (10–200 μm) had no obvious effect on the maximum explosion pressure (Pmax) at a nominal concentration of 130 g/m3. Explosion time (te) and reaction time (tr) of PO aerosol explosion increased with the increase in initial droplet size. The flame propagation process in the direction of 90° was not the same as that of 45°. Explosion flame propagated from the center to the surrounding area, then sagged along wall facing the center and presented a U-shape. Explosion time at ignition temperature of 1600 K was 29.63 ms, which was the shortest compared with the temperature of 2000 K, 2500 K, and 1100 K. The influence of ignition temperature on te was more obvious than that of initial droplet size. The flame propagation mechanism of droplet sizes of 10 μm and 50 μm was different from that of 100 μm and 200 μm. The time to reach the maximum flame temperature(tf) increased with the increase in droplet size; the flame propagation speed decreased with the increasing droplet size, and the maximum flame velocity can reach 6.07 m/s.