CO2 foam was an effective way to regulate CO2 mobility and control the gas breakthrough during the process of CO2 flooding. The poor stability of foam-phase restricted the enhanced oil recovery (EOR) ability of CO2 foam flooding, especially under the harsh reservoir conditions and the challenges are yet to be solved. As such, current work hypotheses that by applying the polymer nanosphere as the additive can extend the foam rupture to increase the foam-phase stability. The acid-resistant hydrophobic polymer nanosphere P(AM-AA-ARM-C16DMAAC) was prepared by the inverse microemulsion polymerization method, which used ARM and C16DMAAC as acid-resistant monomer and hydrophobic monomer, respectively. Then, the CO2 foam reinforced by anionic surfactant AOS and P(AM-AA-ARM-C16DMAAC) was developed, and the stability was compared with conventional foam system using Warning Blender method and high temperature and high pressure electromagnetic coupling agitator. Furthermore, the foam aging rules were investigated via the multiple light scattering method and double-layer glass model to further understand the CO2 foam stability mechanism of synthesized acid-resistant hydrophobic polymer nanospheres. The results demonstrated that P(AM-AA-ARM-C16DMAAC) had good swelling performance under acid environment. With the consistency of 0.2% AOS and 0.15% P(AM-AA-ARM-C16DMAAC), the CO2 foam showed the highest foam stability. The dynamic variations in the film thickness of the foam were characterized quantitatively. The prolonged liquid drainage was attributed to the foam liquid film maintained by released water and the liquid film ‘skeleton’ formed by polymer nanospheres. In addition, the formula of acid-resistant hydrophobic polymer nanospheres P(AM-AA-ARM-C16DMAAC) is adjustable under different environmental conditions. After deformation of the foam system, the polymer nanospheres could also act as plugging agent in the formation.