Abstract: The settlement of machine tool foundations is mainly caused by the shrinkage and creep effects of concrete. When large-scale CNC gantry machine tools are subjected to alternating loads during machining, the presence of workpiece self-weight and machining vibration significantly exacerbates foundation deformation. Such settlement deformation will seriously impair the machine tool’s accuracy and shorten its service life. To accurately predict foundation settlement, this study investigates the shrinkage and creep deformation characteristics of reinforced concrete foundations under variable load conditions based on the B3 model. It adopts the incremental method to calculate concrete stress and creep strain step by step, and then establishes a foundation settlement prediction model. By comparing simulation results with theoretical data, the model’s prediction error is controlled within 6%, verifying its effectiveness. Further research shows that: due to the limitation of reinforcement strain rate, the settlement depth of the reinforced concrete layer is significantly smaller than that of plain concrete, with the maximum reduction rate between adjacent settlement layers reaching 49.9%; under the action of alternating loads, as the variable load amplitude increases, the increase rate of the settlement amount in the upper layer of the foundation can reach 1.13%. This model can not only accurately calculate the settlement thickness, but also achieve compensation control through the prediction of upper-layer settlement amount, providing a theoretical basis for maintaining machine tool accuracy.