Purpose: The wound healing process involves a complex series of biological events. Skin grafts have several uses as a reconstructive method. There are several dressings for the skin graft donor site, but the optimum dressing agents that provide all the requirements at the same time are unclear. This prospective, randomized, placebo-controlled clinical trial aimed to evaluate the therapeutic effect of Zataria multiflora cream in the wound healing process of partial-thickness skin graft donor sites and compared it with a placebo. Materials and Methods: This clinical trial study was performed on patients who underwent split-thickness skin grafts. Enrolled patients applied Z. multiflora cream and placebo controlled (petrolatum ointment) twice a day, from the day of intervention at the skin graft donor sites in two parts, separately. On 7, 14, 21, and 28 days after surgery, the wound healing process was evaluated, photographed, and scored according to the Bates-Jensen assessment tool. Evidence of infection was evaluated. The main agent and placebo were compared during the wound healing process. Results: Decreases in wound surface area and total score were significantly greater in the Z. multiflora group (p < 0.05). The wounds of 30% of patients in the second week and 90% of patients in the third week were completely epithelialized in the Z. multiflora group. These values were 3.3% and 36.7% for the control group, respectively, and so, the healing rate was ∼9-fold in the second week and 2.45-fold in the third week in the Z. multiflora group compared with the control group (p < 0.05). Conclusion: Wound healing and reepithelialization accelerated significantly in the first, second, third, and fourth week after intervention in the Z. multiflora treatment group, due to modulating the inflammatory phase and improving the proliferative phase. Clinical Trial Registration Number: IRCT20210624051695N1.