Medical adhesives have emerged as potential materials for sealing, hemostasis and wound repairing in modern clinical surgery. However, most of existing medical adhesives are still far away from the clinical requirements for simultaneously meeting desirable tissue adhesion, safety, biodegradability, anti-swelling property, and convenient operability. Here, we present an entirely new kind of peptide-based underwater adhesives, which are constructed via cross-linked supramolecular copolymerization between cationic short peptides and glycyrrhizic acid (GA) in an aqueous solution. We revealed the unique molecular mechanism of the peptide/GA supramolecular polymers and underlined the importance of arginine residues in the enhancement of the bulk cohesion of the peptide/GA adhesive. We thus concluded a design guideline that the peptide sequence has to be encoded with multiple arginine termini and hydrophobic residues. The resulting adhesives exhibited effective tissue adhesion, robust cohesion, low cell cytotoxicity, acceptable hemocompatibility, inappreciable inflammation response, appropriate biodegradability, and excellent anti-swelling property. More attractively, the dried peptide/GA powder was able to rapidly self-gel into adhesives by absorbing water, suggesting conveniently clinical operability. Animal experiments showed that the peptide/GA supramolecular polymers could be utilized as reliable medical adhesives for dural sealing and repairing.