| Summary: | Acne is a common skin condition observed in adolescents. Nutmeg (<i>Myristica fragrans</i> Houtt) (MF) is a well-known traditional Chinese medicine; its major toxic components, safrole and myristicin, are rich in essential oils. Essential oils of MF (MFO) were extracted by hydrodistillation; the residue was extracted using 50% methanol (MFE-M). The minimum inhibitory concentration (MIC) of MFE-M against <i>Cutibacterium acnes</i> and <i>Staphylococcus aureus</i> was 0.64 mg. Four compounds were obtained from MFE-M: myristicin (<b>1</b>), (+)-<i>erythro</i>-Δ<sup>8′</sup>-7<i>S</i>,8<i>R</i>- dihydroxy-3,3,5′-trimethoxy-8-<i>O</i>-4′-neolignan (<b>2</b>), (+)-<i>erythro-</i>Δ<sup>8’</sup>-7-hydroxy-3,4,3’,5’-tetramethoxy 8-<i>O</i>-4-neolignan (<b>3</b>), and e<i>rythro</i>-Δ<sup>8′</sup>-7-acetoxy-3,4,3′,5′-tetramethoxy-8-<i>O</i>-4′-neolignan (<b>4</b>). Compound <b>2</b> exerted the strongest antimicrobial activity, with MICs of 6.25 and 3.12 μg/mL against <i>C. acnes</i> and <i>S. aureus</i>, respectively. Moreover, <b>2</b> inhibited NO, PGE<sub>2</sub>, iNOS, and COX-2 levels in RAW 264.7 cells induced by LPS or heat-killed <i>C. acnes</i>; NO production at 50% inhibitory concentrations (IC<sub>50</sub>) was 11.07 and 11.53 μg/mL, respectively. Myristicin and safrole content was higher in MFO than in MFE-M. MFO and MFE-M caused no skin irritation after a single topical application in Wistar rats. MFE-M, with low safrole and myristicin content, did not cause skin irritation and exhibited an anti-acne effect; moreover, <b>2</b> was identified as the active substance. Therefore, MFE-M could be employed to develop anti-acne compounds for use in cosmetics.
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