Acne vulgaris (AV) is one of the top concerns dermatologists encounter from women. Until now, therapies addressing AV have largely centered around, and have been successful at, targeting the pathophysiological mechanisms that occur at the pilosebaceous unit: sebum hypersecretion, follicular keratinization, over-proliferation of Cutibacterium acnes, and a localized immune response. In addition to these, there is good evidence to suggest that other systemic drivers of a generalized inflammatory response may contribute to the development or exacerbation of acne and that addressing these underlying factors may open more opportunities for developing effective treatments. These include psycho-emotional stress, diet and metabolism, hormonal fluctuations, skin and gut microbiome, oxidative stress, and immune response. While there is accumulating evidence that vitamins, minerals, and botanicals may mitigate some of the pro-inflammatory effects from the activation of these underlying systems, their use and recommendations are limited by a lack of quality efficacy and safety evidence. Here, we present the current evidence for the use of individual supplements in addressing the 6 systemic underlying drivers of AV. We also present a clinical study on the safety and efficacy of a nutraceutical combining many of these ingredients in the management of AV in men and women. J Drugs Dermatol. 2024;23(3):160-167 doi:10.36849/JDD.8138.