Background <p>Wound healing and scar formation at skin graft donor sites are major concerns in reconstructive surgery. This study was designed to evaluate the effectiveness of nano-propolis in promoting wound healing at graft donor sites compared to standard Vaseline treatment.</p> Methods <p>A randomized, double-blind prospective clinical trial was conducted with 35 patients undergoing skin grafting at a tertiary center, from September 2020 to September 2021. Each patient had two adjacent graft donor sites treated with either nano-propolis ointment or Vaseline in a randomized fashion. Wound healing was evaluated on postoperative days 1, 3, 7, 14, 21, and 28 using the Bates-Jensen Wound Assessment Tool. Data analysis was performed using SPSS version 26.</p> Results <p>Thirty participants completed the study after exclusions and withdrawals. The participants comprised 60% men and 40% women, with an average age of 50.33 years (range 22–68 years). The most common underlying condition requiring skin grafting was basal cell carcinoma, followed by squamous cell carcinoma. Nano-propolis significantly enhanced wound healing outcomes, including faster wound size reduction, improved epithelialization, and superior Bates-Jensen scores compared to Vaseline (<InlineEquation ID="IEq1"> <EquationSource Format="TEX">\(\:p&gt;0.05\)</EquationSource> </InlineEquation>). No significant differences in infection rates, pain, or other complications were observed between the two treatment methods (<InlineEquation ID="IEq2"> <EquationSource Format="TEX">\(\:p&lt;0.05\)</EquationSource> </InlineEquation>).</p> Conclusions <p>Nano-propolis significantly accelerates wound healing at graft donor sites without increasing adverse outcomes, suggesting its potential as an adjunctive treatment in wound care. Further research is needed to explore its molecular mechanisms.</p> Level of Evidence <p>Level II, therapeutic study.</p>