The uniformity of secondary air (SA) in large-scale CFB boilers has an important influence on gas-solid flow and combustion, but was seldom considered in previous studies. Numerical simulation based on the Eulerian–Eulerian and RNG k-ε turbulence models was conducted to explore the influence of SA uniformity and load variation on jet penetration, diffusion characteristics and gas-solid mixing in the first 600 MW supercritical CFB boiler. The results showed that better SA uniformity was conductive to the uniformity of SA penetration and gas-solid mixing along the furnace height, although the penetration depth and diffusion distance showed an opposite trend. In addition, the penetration depth and diffusion distance got enhanced with higher boiler load. The inner and outer SA jets could not cover the furnace width, and the uneven SA uniformity led to a huge deviation of the solid concentration within 10 m of the air distributor. Eventually, a calculation model was successfully established for predicting the penetration depth of inclined thermal SA jets during boiler operation.