Background Burns represent one of the most prevalent traumatic injuries worldwide, with an estimated annual global incidence of approximately 11 million cases, predominantly affecting low- and middle-income countries. Despite advances in modern wound care, including advanced dressings, skin grafting, and negative pressure wound therapy, the management of partial-thickness burns remains challenging due to prolonged healing times, excessive scar formation, and substantial healthcare costs. Mongolian medicine horse oil rubbing therapy (MMHRT), an ethnomedical practice with over 800 years of documented clinical use in Inner Mongolia, China, has demonstrated promising wound healing outcomes in preliminary clinical observations. However, rigorous evidence supporting its efficacy and mechanistic basis has been lacking. Objective This study aimed to evaluate the clinical efficacy and explore the molecular mechanisms of MMHRT in promoting burn wound healing through a randomized, controlled, parallel-group clinical trial. Methods A total of 120 patients with superficial partial-thickness (IIa degree) burns, aged 18-65 years, with total body surface area (TBSA) involvement of 1-15% and post-injury time within 48 hours, were enrolled and randomly assigned (1:1) to the MMHRT group (n=60) or the standard silver sulfadiazine (SSD) cream group (n=60). Primary outcomes included complete wound healing time and healing rate at days 7, 14, and 21 post-treatment. Secondary outcomes encompassed pain assessment using a visual analog scale (VAS), Vancouver Scar Scale (VSS) scores at 1 and 3 months post-healing, serum inflammatory cytokine levels (TNF-alpha, IL-1beta, IL-6, IL-10), and wound tissue expression of NF-kappaB/TLR4 signaling pathway proteins. Adverse events were monitored throughout the study period. Data were analyzed using intention-to-treat (ITT) principles with appropriate statistical methods. Results The MMHRT group demonstrated significantly accelerated wound healing compared to the SSD group, with median healing time of 14.0 days (IQR: 12.0-16.0) versus 18.0 days (IQR: 16.0-21.0) in the SSD group (P<0.001). The cumulative healing rates at days 7, 14, and 21 were 18.3%, 78.3%, and 98.3% in the MMHRT group, compared with 6.7%, 43.3%, and 85.0% in the SSD group, respectively (all P<0.01). VAS pain scores were significantly lower in the MMHRT group from day 3 onward (P<0.001). VSS scores at 1 month and 3 months post-healing were significantly reduced in the MMHRT group (3.2+-1.4 vs 5.8+-2.1, P<0.001; 1.8+-0.9 vs 4.2+-1.6, P<0.001). Serum levels of pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) decreased more rapidly, while Glob J Clin Trials, 2026 Volume 1| Issue 1| 2 anti-inflammatory IL-10 increased more substantially in the MMHRT group. Western blot analysis revealed that MMHRT significantly suppressed TLR4/NF-kappaB pathway activation and upregulated PPARgamma expression in wound tissues. No serious adverse events were reported in either group. Conclusion MMHRT significantly accelerates burn wound healing, alleviates pain, and improves scar quality compared with standard SSD therapy. The underlying mechanisms involve modulation of the TLR4/NF-kappaB inflammatory signaling pathway, promotion of PPARgamma-mediated anti-inflammatory responses, and optimization of the local wound microenvironment. These findings provide rigorous clinical evidence supporting the traditional application of MMHRT and suggest its potential as a complementary therapeutic option for partial-thickness burn management.