Foam is a kind of ideal fluid for profile control in petroleum engineering, which has attracted intense interests of scholars globally in recent years. In this study, a foam system stabilized with anionic surfactants and clay particles was proposed for profile control in reservoirs, and the formulation was optimized experimentally. Moreover, flooding experiments in visible porous media models and in sandpacks were conducted to test the plugging effect of the foam system on reservoirs, and the effects of different factors such as gas–liquid ratio, temperature and permeability on profile control were also evaluated. According to the experimental results, the clay-HY-2 system was elected for its satisfactory foamability, stability, and salinity resistance, and the optimum concentrations of HY-2 and clay particle are 0.6 wt% and 5.0 wt%, respectively. Compared with traditional foam fluids, the clay-HY-2 system can form denser and smaller bubbles in high- and middle-permeable layers, enhancing the plugging effect there, while there are less bubbles in low-permeable layers, i.e., the restriction on the flow in narrow structures is slight. The clay-HY-2 foam can perform the efficient and uniform profile control effect on sandpacks when the foam quality is around 50%. The resistance factor of the foam decrease gradually with the increasing temperature, however, the resistance factor remains higher than 350.0 when the temperature reaches 80.0 °C. When the permeability exceeds 1502.0 mD, the clay-HY-2 foam can perform deep profile control in reservoirs, and the resistance factor are not sensitive to the change of permeability when it exceeds 3038.0 mD. Besides, the site application case shows that the clay-HY-2 foam do have good profile control effect on reservoirs, i.e., improving oil production and declining water cut.