Surgical-site infection (SSI) is a common postoperative complication, primarily caused by Staphylococcus aureus. S aureus produces hyaluronidase which degrades hyaluronic acid (HA). HA prevents bacterial proliferation and has anti-inflammatory effects to promote wound healing. We evaluated the effect of HA injection with systemic antibiotics for prevention and treatment of SSIs caused by S aureus. An open wound was created on the dorsum of 40 rats. The wound bed was sutured with S aureus inoculated thread. The test group was injected with HA (HA group), and the control group received a subcutaneous injection of normal saline (NS group). All groups were then treated with intraperitoneal cefazolin injection. The sutures were removed 2 days after the procedure. Gross pathology, bacterial count, and wound histology were assessed at days 2, 4, 6, and 8 postprocedure. The HA group showed a significant reduction in the wound area compared with the control group on gross pathology (at days 8 postprocedure, 36.54% ± 6.12% vs 50.59% ± 5.50%, P < .001). The HA group showed significantly better wound healing than the control group on histological analysis, including assessment of abscess, neutrophilic infiltration, and necrosis (4.2 ± 1.2 vs 11.5 ± 2.1, P < .001). The HA group showed a lower bacterial count compared with the NS group, but the result was not significant statistically (at days 6 postprocedure, 5.11 ± 0.31 vs 5.91 ± 0.35 logCFU/mL, P = .706). In conclusion, immediate local injection of HA in wounds can reduce SSI occurrence and promote wound healing in an animal model.