Objectives <p>This study aimed to evaluate the prevalence of isotretinoin use among acne patients and investigate its association with depression, contributing to the ongoing discussion on its psychiatric safety.</p> Materials and methods <p>A cross-sectional study was conducted at Jordan University Hospital’s dermatology clinic, including 386 acne patients without a history of depression. Data were collected through structured questionnaires assessing demographics, acne severity, isotretinoin use, and depressive symptoms using the Center for Epidemiologic Studies Depression Scale (CES-D). Statistical analyses, including <i>t</i>-tests, ANOVA, Pearson’s correlation, and multiple linear regression, were used to explore associations.</p> Results <p>Isotretinoin use was reported by 41.2% of participants. No significant association was found between isotretinoin use and depression (<i>p</i> = 0.456). However, female gender (<i>p</i> = 0.001) and prolonged acne duration (<i>p</i> = 0.034) were significantly associated with higher CES-D scores. Acne severity (<i>p</i> = 0.892) showed no significant correlation with depression.</p> Conclusions <p>This study found no evidence linking isotretinoin use to depression among acne patients. Given that acne severity and duration were accounted for, our findings suggest that if isotretinoin influences depression, its effect is likely mediated through acne improvement rather than direct neuropsychiatric effects. Additionally, female gender, family history of depression, prolonged acne duration, and social isolation were associated with higher depression scores. These findings support the mental health safety of isotretinoin but emphasize the need for individualized patient monitoring, particularly for those with depression risk factors.</p>