<b><i>Background:</i></b> Dupilumab ameliorates the signs and symptoms of atopic dermatitis (AD) and improves the patient’s quality of life. Multiple-dose regimens of dupilumab have been applied by clinicians, but the efficacy of some regimens remains unclear. <b><i>Objectives:</i></b> The aim of the study was to systematically evaluate the efficacy and safety of multiple dupilumab dose regimens in patients with moderate-to-severe AD in terms of comprehensive outcomes. <b><i>Methods:</i></b> We searched electronic databases and subjected the selected studies to risk-of-bias assessment and network meta-analysis (NMA). Efficacy and safety outcomes were compared using a random-effects NMA to estimate pooled relative risk ratio (RR) of direct and indirect comparisons among multiple dupilumab dose regimens. The Eczema Area Severity Index, Investigator’s Global Assessment, and pruritus numerical rating scale were analyzed to assess the efficacy, while adverse events (AEs) and serious adverse events to represent the safety. <b><i>Results:</i></b> Eight randomized controlled trials involving 3,679 patients were identified. Most patients received therapy for 16 weeks. Multiple dupilumab dose regimens, including 300 mg weekly (QW), 300 mg every 2 weeks (Q2W), 200 mg Q2W, 300 mg monthly (QM), 300 mg every 2 months (Q2M), and 100 mg QM were analyzed. All regimens, except 100 mg QM, had significantly better efficacy than placebo. 300 mg QW and 300 mg Q2W appeared to have similar efficacy. Notably, both 300 mg QW and 300 mg Q2W had no significantly better efficacy than 300 mg QM. As for 300 mg Q2M, significantly reduced efficacy was noted in only one efficacy outcome when compared to 300 mg QW and 300 mg Q2W. In terms of safety outcomes, AEs occurring with any of the regimens were comparable with the placebo. No significant inconsistency was noted within the network in all efficacy outcomes. <b><i>Conclusions:</i></b> Our NMA indicated that the administration of the following dupilumab regimens was effective for patients with moderate-to-severe AD: 300 mg QW, 300 mg Q2W, 200 mg Q2W, 300 mg QM, and 300 mg Q2M. Our data can improve the understanding of the relative efficacy and safety of multiple dupilumab dose regimens, which will help in shared decision-making between clinicians and patients.