Background Systemic isotretinoin is the most effective treatment for acne vulgaris (AV). However, numerous side effects are associated with isotretinoin. Oral zinc has a better safety profile and has been used to treat AV with variable results. Objective We sought to evaluate the safety and efficacy of combining oral zinc to low-dose systemic isotretinoin in AV patients. Methods Sixty AV patients were divided into two groups. Group A received oral zinc sulfate plus low-dose isotretinoin and Group B received the standard isotretinoin dosage. At each visit acne severity, photos, side effects, and patient-reported satisfaction were recorded. Results In the two groups, no significant difference in reduction of lesion count and Global Acne Grading System scores. The frequency of treatment-related side effects was (20%) in Group A and (76.7%) in Group B. Furthermore, there was no difference regarding the relapse rates between both groups (p>0.05). Finally, the patients’ satisfaction rates did not differ between the two groups. Conclusion Oral zinc plus low-dose isotretinoin resulted in satisfactory improvement in AV patients with fewer side effects. Further studies are recommended to compare the efficacy of other zinc preparations if combined with systemic isotretinoin at different concentrations