In this study, a strategy towards thermoplastic-metal hybrid joint via bidirectional modification for high reliability was designed. The chemical bond behavior and conditions at the interface were explored from atomic scale using density functional theory (DFT) calculation. Based on the bonding mechanism, the AZ31B alloy was oxidized and the carboxyl groups (COOH) were introduced in the resin chain to improve the strength of chemical bond. The mechanical property of the designed joint was significantly improved and the tensile-shear strength achieved 22.7 MPa after bidirectional modification, reaching 4.5 times that of untreated joints. It was mainly attributed to the generation of metal-carboxylate bridging complex—a typical strong coordination bond formed between two O atoms in COOH and two diagonal magnesium atoms in MgO. Experimental evidence also suggested the generation of new chemical bond at the CFRTP/AZ31B interface. Finally, the bidirectional modification was proved to be an efficient and reliable method with high industrial adaptability. The current work opened up a novel direction for reliability promotion of thermoplastic-metal hybrid structures.