Isotretinoin (ISO) is an oral prescription-only retinoid, well known for its acne-treating effect. However, it affects a substantial number of human cell types, causing a broad spectrum of adverse effects. The purpose of this study is to establish the isotretinoin therapy adverse events among human clinical trials and their prevalence. Two authors (J.K., J.L.) systematically performed the literature review and assessment from December 2021–February 2022. Three databases (PubMed, ClinicalTrials, and Cochrane Library) were searched using the following terms: “isotretinoin acne vulgaris” for published studies in English from 1980–2021. Finally, 25 randomized controlled clinical trials (RCTs) and five open-label clinical trials provided 3274 acne vulgaris suffering patients. Isotretinoin therapy affects almost all of the systems in the human body, causing numerous adverse events. However, they mainly concern mild mucocutaneous conditions (severe cases are rare) and represent individual responses to a drug. In addition, all adverse events are reversible and can be avoided by specific preparations.