AbstractUnhealed wound after malignant skin tumor resection, characterized by full‐thickness cutaneous defects, large open cavities, and incomplete tumor tissue resection are the leading cause for long recovery times, poor prognoses, and high recurrence among patients. Herein, a hyaluronic acid (HA)‐based microneedle (MN) functionalized with biomineralized melanin nanoparticles is fabricated to concurrently administer tumor photothermal therapy (PTT) and promote skin tissue regeneration. Natural melanin nanoparticles derived from cuttlefish ink (CINP) possessing antioxidative and photothermal functionalities are employed to scavenge ROS and implement PTT. Further, CINPs are encapsulated within an amorphous silica shell that served as a source of bioactive to stimulate skin tissue regeneration. Due to the physical penetration characteristics of microneedles, the obtained CINP@SiO2‐HA MNs could exert photothermal eradication of the remaining subcutaneous tumor cells to avoid recurrence and inhibit Staphylococcus aureus infection in wound beds. Moreover, benefiting from ROS‐scavenging and release, inflammatory environment can be well controlled and angiogenic gene expression can be up‐regulated for skin tissue regeneration. With requisite biofunctionality, convenient synthesis, and excellent biocompatibility, CINP@SiO2‐HA MNs accompanied with clinically feasible irradiation meet the multiple demands of tumor eradication and wound healing, holding great potential as a supplementary therapy following skin tumor resection.