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This study aimed to develop propolis and tea tree oil nanoemulsion loaded with clindamycin hydrochloride to heal wound effectively. Nanoemulsion formulae were prepared and characterized by droplet size analysis, zeta potential, viscosity, ex-vivo permeation, and skin deposition. The optimal formula was evaluated in terms of morphology, cytotoxicity, and in-vitro wound healing assay. Also, the efficacy of the optimal formula was evaluated by in-vivo wound healing and histopathological studies. The optimal formula (F3) was composed of 9% tea tree oil and 0.4% propolis extracts with mean droplet size 19.42 ± 1.7 nm, zeta potential value −24.5 ± 0.2 mV, and viscosity 69.4 ± 1.8 mP. Furthermore, the optimal formula showed the highest skin deposition value 550.00 ± 4.9 µg/cm 2 compared to other formulae. The TEM micrograph of the optimal formula showed that the nanoemulsion droplet has an almost spherical shape. Also, the optimal formula did not show noticeable toxicity to the human skin fibroblast cells. The in-vitro and in-vivo wound healing assay showed unexpected results that the un-loaded drug nanoemulsion formula had a comparable wound healing efficacy to the drug-loaded nanoemulsion formula. These results were confirmed with histopathological studies. Our results showed that the propolis and tea tree oil nanoemulsion, whether loaded or unloaded with an antibiotic, is an efficient local therapy for wound healing.