Polydeoxyribonucleotide (PDRN) is known to enhance wound healing, but there has been no clinical trial investigating the effect of PDRN on scar prevention in surgical wounds. This study aimed to evaluate the efficacy of PDRN administration in preventing postoperative scars. In this randomized controlled trial (NCT05149118), 44 patients who underwent open thyroidectomy were randomly assigned to the PDRN treatment or untreated control group. Only patients in the treatment group received two consecutive injections of PDRN 1 and 2 days after surgery. The modified Vancouver Scar Scale (mVSS), patients' subjective symptoms, erythema index (EI), melanin index (MI), and scar height were assessed 3 months after surgery. Patients in the treatment group had lower mVSS scores (1.619 ± 1.244 vs. 2.500 ± 1.540, respectively;  = 0.059) and a significantly lower vascularity subscore (0.476 ± 0.512 vs. 0.900 ± 0.447, respectively;  = 0.010) than those in the control group at the 3-month follow-up. Compared with the control group, the level of subjective symptoms, EI, and scar height were all significantly lowered in the PDRN injection group. No specific side effects related to PDRN injection were observed. This is the first clinical study that demonstrated that PDRN injections rapidly decreased postsurgical wound erythema and as a result, significantly reduced both excessive scar formation and accompanying symptoms. Early postoperative injection of PDRN is an effective and safe treatment to prevent hypertrophic scars and improve scar outcomes.