To solve the problem of poor adhesion of the coating/metal interface in deep-sea environments, active epoxy resin (ZA-EP) was prepared by grafting histamine onto the epoxy resin E44 molecular chain, which can facilitate the formation of chemical bonds with metal substrate. Histamine heteroatoms in ZA-EP can form a shared lone pair electron with the vacant orbital of iron/iron oxide, which can promote the formation of the complex of Fe²⁺ ions with the resin, thus improving the interfacial bonding strength between the coating and the metal substrate. Compared with the ordinary epoxy coating, the adhesion of the coating containing active resin was significantly improved: for example, the adhesion of epoxy coating increased from 6.02 MPa to 15.36 MPa after the addition of 3% ZA-EP. In addition, the test results in the simulated deep-sea water under alternating pressure show that the saturation water absorption of the 3% ZA-EP/EP coating is the lowest, only 1.6% after one cycle test in 3.5%NaCl solution (by high static pressure 3.5 MPa for 12 h + constant pressure 0.1 MPa for 12 h). The EIS results after 3 cycle test (72 h) showed that the impedance of the 3%ZA-EP/EP coating remained stable. In other words, histamine modification may facilitate the formation of a chemical bond at the coating/metal interface, enhances the adhesion of the coating, thereby, the ZA-EP/EP coating has a good protective performance.