Chronic inflammation impedes the healing of diabetic ulcers (DUs), while P-glycoprotein (P-gp)-mediated drug efflux reduces the efficacy of conventional drug formulations. In this study, a novel liposome-mediated hyaluronic acid (HA) microneedle patch (E-Lipo@A-HMN) was developed for enhanced DUs healing via the transdermal delivery of Acetyl-11-keto-β-boswellic acid (AKBA) and β-elemene (ELE). The findings demonstrate that liposomal encapsulation enhances the solubility and bioavailability of ELE, and HA microneedles improve skin penetration and enable controlled drug release by providing a biodegradable, biocompatible scaffold that improves skin penetration and enables controlled drug release. Furthermore, our treatment protocol could effectively attenuate inflammation and promote fibroblast proliferation, collagen deposition and angiogenesis by inhibiting P-gp expression, enhancing intracellular drug accumulation and downregulating the PI3K/AKT/NF-κB signaling pathway. Compared to conventional therapies, E-Lipo@A-HMN exhibits better therapeutic performance, demonstrating enhanced anti-inflammatory activity and accelerated wound repair. Moreover, the treatment protocol displays an excellent biosafety profile. It offers a novel, safe, and effective therapeutic strategy for treating DUs with significant potential for clinical application.