AbstractSelf‐adaptive hydrogels that can specifically respond to pathological cues and match the highly ordered tissue regeneration process are significantly on‐demand for effective wound management. Herein, multifunctional marine‐derived gold clusterzyme (AuNCs)‐based self‐adaptive hydrogels with microenvironment triggered release behavior are elaborately fabricated for on‐demand antioxidant, anti‐inflammatory and immunoregulation. The marine mussel‐derived catechol ligands (L‐3,4‐dihydroxyphenylalanine) endow AuNCs with enhanced superoxide dismutase‐mimic activity due to their high affinity to superoxide anion free radical (O2−•) and unique electron transfer mechanism, leading to 100% inhibition of O2−•. Upon uniformly crosslinking with phenylboronic acid‐modified marine‐derived sodium alginate (PBA‐Sa), the obtained AuNCs@PBA‐Sa hydrogels exhibit outstanding self‐healing property, tunable degradation and good removability. Meanwhile, AuNCs can greatly enhance the mechanical property and confer the hydrogel with favorable tissue adhesion for rapid hemostasis. Furthermore, injectable AuNCs@PBA‐Sa hydrogels can not only adapt their shape to the irregular wound, but also smartly adapt their microstructure to the physiological microenvironment of diabetic wound, leading to the responsive release of AuNCs upon the break of boronate ester bonds. The released gold clusterzymes can actively induce the generation of M2‐macrophage, demonstrating an outstanding anti‐inflammatory and pro‐regeneration effect. Therefore, the present multifunctional clusterzyme‐based self‐adaptive hydrogels hold great potential for remolding the dynamic tissue regeneration microenvironment and smart wound management.