Dupilumab is a biologic therapy approved for the treatment of various chronic inflammatory conditions. Clinically, it has been used in combination with other biologic agents for patients who are refractory to biologic monotherapy or who require immunotherapy for multiple conditions. However, the safety and efficacy of such combinations remain unclear. Our objective is to evaluate the safety profile, adverse effects (AEs), and clinical outcomes in these patients. A systematic search of Ovid MEDLINE, EMBASE, PubMed, and Web of Science was conducted from inception to April 2024. English-language primary studies assessing patients treated with dupilumab and at least 1 other biologic agent were included. Additional studies were identified through citation chaining and handsearching. A total of 27 studies comprising 156 patients were analyzed. A total of 51.9% were treated for a single condition and 48.1% for comorbid conditions. The most common indications for combination biologic therapy were respiratory (34.7%) and dermatologic (73.3%) disorders. Mild AEs were reported in 94.9% of cases, with injection site reactions, upper respiratory tract infections, and headaches being the most frequent. Serious AEs were rare, and none were directly attributed to biologic therapy. Clinical outcomes were generally favorable, with improved disease control observed in 62.1% of cases. Combination biologic therapy with dupilumab is well-tolerated in select patients, suggesting promising efficacy in addressing comorbid conditions, refractory disease, and AEs from monotherapy. Long-term effects and disease-specific AEs remain unclear. Additional research is needed to determine the efficacy and safety profiles of specific biologic combinations.