Postoperative delirium (POD) is an acute mental disorder that occurs after surgery requiring general anesthesia. In animal studies, high-mobility group box 1 (HMGB1) plays a key role in mediating postoperative neuroinflammation and may have a direct impact on POD. The objective of this prospective observational study was to investigate the serum levels of HMGB1 in elderly POD patients undergoing total hip arthroplasty. This prospective observational study included 287 elderly patients who underwent total hip arthroplasty in our hospital from October 2019 to September 2022. Patients were assessed for the presence of POD using the Confusion Assessment Method (CAM) within 72 h of surgery. Serum HMGB1, interleukin (IL)-6, IL-1β, tumor necrosis factor alpha (TNF-α), and C-reactive protein (CRP) levels were measured using enzyme-linked immunosorbent assay (ELISA) before surgery, as well as at 24 h, 48 h and 72 h after surgery. Demographic and clinical data of all elderly patients were collected. The anesthesia time and surgical time in the POD group were significantly higher than those in the non-POD group. The serum levels of HMGB1, IL-6 and IL-1β in the POD group were significantly elevated compared to those in the non-POD group at all time points after surgery (p < 0.05). In addition, the serum levels of HMGB1 were positively correlated with TNF-α, IL-6 and IL-1β levels. HMGB1, IL-6 and IL-1β could be potential predictive biomarkers for the occurrence of POD in elderly patients undergoing total hip arthroplasty. Finally, we found that anesthesia time, surgical time, HMGB1, TNF-α, IL-6, and IL-1β were risk factors for POD in elderly patients undergoing total hip arthroplasty. Serum HMGB1 levels were markedly elevated in elderly POD patients undergoing total hip arthroplasty. In addition, HMGB1 could serve as a potential predictive biomarker for POD in elderly patients undergoing total hip arthroplasty.