<p>Acne vulgaris (AV) is a common, long-lasting skin condition characterized by inflammation that is frequently linked to the bacteria <i>Cutibacterium acnes</i> (<i>C. acnes</i>) and <i>Staphylococcus</i> spp. Conventional medicines face difficulties, such as bacterial resistance, in treating acne vulgaris, highlighting the need for new treatment approaches. In this study, we investigated the antibacterial activity of three medicinal plants, <i>Garcinia mangostana</i> (<i>GM</i>), <i>Curcuma comosa</i> (<i>CC</i>), and <i>Acanthus ebracteatus</i> (<i>AE</i>), which are traditionally used to treat different illnesses because of their antibacterial, antioxidant, and anti-inflammatory properties. We utilized a mix of in silico, in vitro, and molecular dynamics (MD) techniques to assess their abilities to treat skin breakouts. We found that the active ingredients in these herbs significantly interact with several bacterial and human inflammatory proteins. Specifically, the herbal components strongly bind to the bacterial enzyme topoisomerase II alpha (TOP2α), which is fundamental for bacterial DNA replication and repair, as well as to human nuclear factor kappa B subunit 1 (NFκB1), which is a vital marker of inflammation. The findings from this study suggest that this combination treatment offers two advantages, preventing bacterial growth and reducing inflammation, making it a promising choice for skin breakouts. In addition, this combination was not toxic to fibroblasts, supporting its capacity as a safe skin treatment. Interestingly, at a 15:5:10 <i>GM</i>:<i>CC</i>:<i>AE</i> ratio, this combination treatment displayed high selectivity indices (SIs) against <i>Staphylococcus epidermidis</i> (26.87) and <i>C. acnes</i> (4.99), indicating its strong therapeutic potential without side effects. In conclusion, our study highlights that this combination is a novel, effective, and safe choice for controlling acne vulgaris, especially because of its ability to inhibit TOP2α and regulate NFκB1.</p>