The bonding effects of EDTA-chitosan, phosphoric acid, and SE-Bond were compared.Material synthesis, Fourier transform infrared spectroscopy, transmission electron microscopy, scanning electron microscopy, laser confocal microscopy, microtensile bond strength, stereomicroscope observation section, CCK8 cytotoxicity assay, and microfluidic experiments were applied.EDTA-chitosan was synthesized, and it was found by transmission electron microscopy that the application of EDTA-chitosan to dentin can extrafibrillarly demineralize collagen fibers. Scanning electron microscopy provided evidence for the retention of smear plugs in dentin conditioned with 1 wt% EDTA-chitosan. Mixed layer and long resin protrusions can be formed after bonding under a laser confocal microscope. The microtensile strength test found that the bonding strength and the durability obtained by applying the chelating agent EDTA-chitosan to dentin were equivalent to SE-Bond and better than the phosphoric acid wet bonding commonly used clinically (P < 0.05). The cytotoxicity of EDTA-chitosan was lower than that of phosphoric acid and SE-Bond in the CCK-8 assay and lower than that of phosphoric acid in the microfluidics experiment.Taken together, the EDTA-chitosan extrafibrillar demineralization strategy retains intrafibrillar minerals and provides better bonding strength and durability with lower cytotoxicity.EDTA-chitosan has the potential to be applied to dentin resin for direct bonding restoration and has good clinical application prospects.