While early excision and grafting has revolutionized burn wound care, autologous split-thickness skin grafts are sometimes unavailable. Tissue-engineered skin substitutes have generated great interest but have proven inadequate. Therefore, the development of novel biomaterials to replace/augment skin grafting could improve burn patient outcomes. Herein, we establish the effects of debridement on deep-partial thickness burns and subsequently examine the effects of 3 different hydrogels on healing. Burns were created on the dorsum of pigs and 4 days after, the eschar was either left intact or debrided for treatment with collagen, PEGylated fibrinogen (PEG-fibrin) or PEGylated autologous platelet-free plasma hydrogels. Wounds were photographed, scored, and biopsied for histology on postburn days 7, 10, 14, and 28. Compared with nondebrided wounds, debridement improved wound color and suppleness but accelerated contraction. Debridement also significantly reduced the number of neutrophils in the wound bed at days 10 and 14 postburn. Treatment with any hydrogel transiently mitigated contraction, with the PEG-fibrin group displaying less contraction on day 28. All hydrogels were visible histologically for up to 10 days, with significant cellular and blood vessel infiltration observed in PEG-fibrin hydrogels. Collagen and PEG-fibrin hydrogels reduced neutrophils and macrophages in surrounding granulation tissue on day 7 and the PEG-fibrin hydrogels containing less immune cells. These data suggest that a single hydrogel application at the time of debridement has immunomodulatory properties that aid in wound healing. Ultimately, these hydrogels may be combined with other biomaterials, cells, or biologics for replacing/augmenting skin substitutes.