Porosity, permeability, and wettability are crucial factors that affect the oil–water displacement process in reservoirs. Under subsurface conditions, the integral effects of these factors are extremely difficult to document. In this paper, waterflooding experiments were carried out using a core flooding system monitored with X-ray dual-energy CT. The mesoscale, three-dimensional characteristics of water displacing oil were obtained in real time. The integral effects of porosity, permeability, and wettability on the waterflooding in the low-permeability sandstone reservoirs were investigated. It was found that if the reservoir rock is water-wet, then the residual oil saturation decreases gradually with increasing porosity and permeability, showing an increasing waterflooding efficiency. On the contrary, if the reservoir rock is oil-wet, the residual oil saturation gradually increases with improving porosity and permeability, showing a decreasing waterflooding efficiency. The porosity, permeability, and wettability characteristics of reservoirs should be comprehensively evaluated before adopting technical countermeasures of waterflooding or wettability modification during oilfield development. If the porosity and permeability of the reservoir are high, water-wet reservoirs can be directly developed with waterflooding. However, it is better to make wettability modifications first before the waterflooding for oil-wet reservoirs. If the porosity and permeability of the reservoir are poor, direct waterflooding development has a better effect on oil-wet reservoirs compared with the water-wet reservoirs.