Compressive strength of cement stone is crucial to ensuring the cement sheath sealing integrity of oil and gas wells. Nanomaterials can improve the mechanical properties of oil well cement effectively. However, due to the small particle size and large van der Waals force of nanomaterials, they are easy to agglomerate, which limits their reinforce effect. In this work, a sub-micron spherical silica with a D50 of 186 nm is developed to improve the compressive strength of cement stone in oil wells. Particle size analysis showed that about 21% of the sub-micron silica particles have a particle size of less than 100 nm, which partially possesses the characteristics of nanomaterials. Due to the particle size of most of the particles being greater than 100 nm, the van der Waals force between particles is weakened compared to nanometer material. The results indicate that the compressive strength of cement stone under dry mixed, wet mixed, and ultrasound-assisted dispersion mixed conditions is similar. The SEM photo of cement stone also indicates that the particles less than 100 nm are well dispersed and rarely agglomerated. Rheology experiments show that the sub-micron spherical silica has little effect on the rheological properties of cement slurry. Mechanical experiments show that 7 d compressive strength improvement rate of cement stone can reach to 18.2% at 80℃. MIP data indicate that the sub-micron spherical silica has significant effect in filling pores and reducing the porosity of cement stone. The sub-micron spherical silica applied in this work has a significant improvement effect on the compressive strength of cement stone, and the particles are easy to aggregate. It has good application prospects as it has no negative impact on mixing, rheology, thickening and other properties of cement slurry.