X-ray imaging in combination with image registration was employed to unveil the microstructure alteration of defective wellbore cement cores when exposed to stagnant or flowing CO2-saturated brine under geologic carbon sequestration conditions. A varying-radius pipeline (VRP) modeling approach is proposed for estimating the permeability alteration from computed tomography (CT) images of artificial channels in the cement cores. The VRP model simplifies the three-dimensional channels into varying-radius pipelines, solves the problem of flow with one-dimensional Navier‒Stokes equations, and can readily be coupled with the Cahn–Hilliard equation to address multiphase flow problems. Furthermore, the accuracy of VRP modeling was verified by permeability testing and direct pore-scale modeling. The channel after CO2 exposure in the reactive-diffusion process was covered by substantial precipitation of calcite, and the measured channel permeability decreased by 28.67% from the original value 4.15 × 10−8 m2. In contrast, the channel after CO2 exposure in the reactive-flow process underwent significant dissolution, substantial tensile microfractures occurred at channel surface, and the measured channel permeability increased by 8.18% from the original 3.91 × 10−8 m2. The CT image–based microstructure investigation implied that when exposed to immobile CO2-saturated brine, even large fluid channels in wellbore cement may be shielded from further degradation; however, when encountering flowing CO2-saturated brine, cement with large fluid channels may fail. The proposed VRP model has the potential to assess field-scale CO2 leakage in wells.