Determination of postmortem interval (PMI) is one of the goals of the forensic autopsy. The study aimed to correlate the postmortem skin changes and High-mobility group box-1 (HMGB1) alterations in serum and skin immunohistochemical staining with time since death. We used animal and human specimens; forty adult male albino rats were dissected to obtain samples at PMI (0, 3, 6, 12, 24 h); forty human medicolegal autopsy cases with a known time of death (within the first 24 h PMI). Cases were classified into 5 groups according to the PMI: I (0 h); II (≤3h); III (4 to 6); IV (7 to 12); V (13 to 24) hour intervals after death; blood and full-thickness skin samples were collected from both models. Results showed a significant time-dependent elevation in serum HMGB1 levels along with its overexpression in immunohistochemically stained skin tissue. Also, the degree of histopathological changes in epidermis, dermis, and hypodermis progressively increased with PMI in both models. The timetable of postmortem skin histological changes, serum HMGB1 concentration, and immunoexpression for HMGB1 proteins in skin tissues has a profile that could serve as actual and simply convenient parameters for accurate determination of postmortem intervals in both models. HMGB1 displayed a pivotal role in the estimation of PMI at the examined periods. Keywords High-mobility group box 1; Skin;Autolysis; Postmortem changes; Immunohistochemistry