Adhesive polysaccharide gels have highlighted their potential in biomedicine, tissue engineering, and wearable/implantable devices due to their tissue adhesive nature and excellent biocompatibility. However, the weak adhesive strength caused by the unclear relationship between the structure and the adhesive properties seriously hinders their further practical application. Here, a facile one-step synthesis method for adhesive and self-healing hydrogels with chondroitin sulfate (CS) and poly (methyl chloride quarternized N,N-dimethylamino ethylacrylate) (PDMAEA-Q) by ultraviolet light irradiation has been presented. We investigate the mechanism of the adhesion enhancement including improving the mechanical strength of gels (cohesion) and gel/substrate interfacial interactions (interfacial adhesion) by tailoring the compliance and cohesive energy density of the gel. The resultant soft and viscoelastic hydrogels displayed favorable adhesion ability on various substrates, and the adhesive strength to the iron substrate and porcine skin can reach 49.4 kPa and 15.4 kPa, respectively. Additionally, the gels also exhibited rapid self-healing properties and good cytocompatibility. We believe that the adhesive PDMAEA-Q/CS gel would be an ideal candidate for hydrogel glues for human–machine interfaces and biological tissues, and this design idea can open a new path for the preparation of adhesive polysaccharide hydrogels.