OBJECTIVE: To prepare a dissolvable microneedle (MN) patch loaded with sodium houttuyfonate (SH) combined with erythromycin (ERY) (SH + ERY-MN patch), to characterize its properties, and to investigate its synergistic anti-acne effects and the mechanisms involved. METHODS: The SH + ERY-MN patch was prepared by two-step centrifugation. The morphology and skin puncture performance of the microneedles were evaluated using scanning electron microscopy, puncture tests, and other methods. The combined antibacterial effect was assessed using the checkerboard assay. The in vitro anti-inflammatory effect of the SH + ERY-MN patch was evaluated by quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA). The therapeutic effect of the SH + ERY-MN patch on acnes in mice was investigated using an animal model. RESULTS: The microneedle patch prepared in the study had well-aligned microneedles, excellent needle shape, and good mechanical properties, which could effectively penetrate the skin to reach the superficial dermis. The minimum inhibitory concentration (MIC) of ERY against acne was 1.28 mg/mL. When ERY was combined with SH, the results showed that the fractional inhibitory concentration (FIC) was 0.375, indicating that the medication combination had a synergistic antibacterial effect. In particular, the MIC value of ERY in combination was 1/4 of that of ERY used alone. The results of CONCLUSION: SH + ERY-MN patch was successfully prepared and demonstrated obvious anti-acne effects. The SH + ERY-MN patch enhances the transdermal delivery of SH combined with ERY. It provides an innovative method for acne treatment and creates new possibilities for achieving effective drug delivery and improving therapeutic efficacy.