Inflammatory signaling pathways, such as p38 mitogen-activated protein kinase (MAPK) play a central role in host responses to injury. In previous studies by the authors, topical p38 MAPK inhibitors effectively attenuated inflammatory signaling in a partial-thickness scald burn model, when applied to the burn wound immediately after injury. However, clinically relevant full-thickness scald burn wounds may act as a barrier to topical immune modulators, and delayed application of topical p38 MAPK inhibitors may not be effective. In this study, the authors evaluate the efficacy of topical p38 MAPK inhibition on full-thickness scald burns with immediate and delayed treatment. C57/BL6 mice received “Sham” or 30% TBSA full-thickness scald burn injury. After injury, the burn wounds were treated with a topical p38 MAPK inhibitor or vehicle. The treatment group received topical p38 MAPK inhibitor either immediately after burn or 4 hours (delayed) after injury. All animals were killed at 12 or 24 hours. Burn wounds underwent histological analyses. Skin and plasma were analyzed by enzyme-linked immunosorbent assay or real-time quantitative polymerase chain reaction for cytokine expression. Full-thickness scald burns resulted from immersion in 62°C water for 25 seconds. Topical p38 MAPK inhibitor attenuated dermal interleukin (IL)-6, MIP-2, and IL-1β expression and plasma IL-6 and MIP-2 cytokine expression. In addition, delayed application of topical p38 MAPK inhibitors significantly reduced dermal and plasma cytokine expression compared with vehicle control. Topical p38 MAPK inhibitors remain potent in reducing full-thickness burn wound inflammatory signaling, even when treatment is delayed by several hours postinjury. Topical application of p38 MAPK inhibitor may be a clinically viable treatment after burn injury.