Thermosetting epoxy polymers can be designed with recycling, remodeling, and repairing properties owing to the special bond exchange reactions (BERs) in their covalent adaptable networks (CANs). However, the mechanisms behind their complex coupling of hydrodynamic diffusion, molecular reactions, and topological network structure changes have not been fully understood. In this paper, a hydro-chemo-mechanical coupling model is developed to describe self-toughening mechanisms of thermosetting epoxy polymers, wherein the CANs cooperatively undergo the combined processes of hydrodynamic diffusion, chemical BERs, and mechanical topology entanglements. Based on free volume theory and rubber elasticity theory, an extended phantom network model is developed to investigate the synergistic effects of hydrodynamics, BERs, and mechanical topology on interfacial welding and self-toughening behaviors of the CANs. A constitutive stress–strain relationship is further developed to understand the self-toughening mechanisms of CANs undergoing the hydro-chemo-mechanical coupling. Finally, the effectiveness of the proposed model is verified using the results obtained from the experiments and finite element analysis.