OBJECTIVE: To explore the efficacy and safety of pulsed laser-activated injectable hydrogel for combined photodynamic and photothermal therapy of hypertrophic scars. METHODS: In this prospective study, indocyanine green (ICG) was used as a photosensitizer combined with hyaluronic acid (HA) to prepare ICG-HA hydrogel, and its photodynamic and photothermal properties were evaluated. The ex vivo photothermal experiments were conducted to assess the thermal effects on tissue integrity as a preliminary evaluation of safety. Human umbilical vein endothelial cells (HUVECs) were used as the experimental cell model to evaluate the in vitro effects of ICG-HA hydrogel under different therapies. A rabbit ear scar model (n = 36) was established and randomly divided into 6 groups: ICG-HA hydrogels + single-pulse irradiation, single-pulse irradiation, ICG-HA hydrogels + continuous-pulse irradiation, continuous-pulse irradiation, ICG-HA hydrogels and control (n = 6/group). Scar characteristics were monitored at 0, 1, 3, and 5 weeks using Ultrasound Doppler, colorimetry, VSS, and SEI assessments. At 1 and 5 weeks after ICG-HA hydrogels injection, histopathological analyses (hematoxylin and eosin (HE) staining, Masson's trichrome staining (MASSON) and CD31 immunohistochemical staining) were performed. RESULTS: The ICG-HA hydrogel exhibited favorable photodynamic and photothermal properties while maintaining structural integrity during laser therapy. In vitro cell experiments, using CCK-8 for metabolic activity and live/dead staining for membrane integrity, demonstrated that the combined PDT and PTT treatment significantly reduced cell metabolic activity and induced cell death compared to either PDT or PTT alone (P < 0.001). In the rabbit ear scar model, the VSS results showed that at 3 and 5 weeks post-treatment, both the ICG-HA hydrogels + single-pulse irradiation group and the ICG-HA hydrogels + continuous-pulse irradiation group had significantly lower VSS scores compared to the control group (P < 0.05), with the ICG-HA hydrogels + single-pulse irradiation group showing a more pronounced reduction (P < 0.01 at 3 weeks and P < 0.001 at 5 weeks). The similar trends were observed in the SEI scores. Colorimeter analysis revealed that, compared with the control group and the single-pulse irradiation group, the ICG-HA hydrogels + single-pulse irradiation group exhibited significantly lower color difference scores at 1, 3, and 5 weeks post-treatment (P < 0.001, P < 0.01 and P < 0.001, respectively). HE staining results showed that, at 1 and 5 weeks post-treatment, the ICG-HA hydrogels + single-pulse irradiation group had the most significant reduction in scar thickness compared with all other groups (P < 0.001). MASSON results indicated that, at 1 week post-treatment, the ICG-HA hydrogels + single-pulse irradiation group exhibited more orderly collagen alignment with significant consistency and sparser collagen distribution. CD31 immunohistochemical staining results demonstrated that, at 1 and 5 weeks post-treatment, the ICG-HA hydrogels + single-pulse irradiation group significantly reduced vascular density within the scar tissue (P < 0.001). CONCLUSIONS: The ICG-HA hydrogel can effectively and safely synergize PDT and PTT to improve hypertrophic scar conditions under pulsed laser irradiation, especially single-pulse irradiation. This approach provides valuable reference for the clinical treatment in scar treatment.