Eosinophilic esophagitis (EoE) is a chronic inflammatory disease of the esophagus affecting both children and adults, with debilitating and progressive symptoms. EoE has shown an explosive epidemiological rise in the past few decades. Many patients experience a poor level of disease control despite maximal use of available guideline-based therapies, which seriously hampers their quality of life. Diet restrictions and systemic and topical corticosteroids are the current mainstays of EoE therapy, but are associated with significant efficacy, treatment compliance, and safety issues such as oral or esophageal candidiasis, growth retardation, osteopenia, osteoporosis, glucose intolerance, and cataract formation. As EoE is a chronic inflammatory disease, immune cells and cytokines are responsible for the inflammatory response and symptoms. Monoclonal antibodies specifically targeting these pathophysiologic effectors offer more potent relief of histologic and clinical disease features while keeping off-target adverse effects to a minimum. Herein, we have reviewed the current evidence regarding efficacy and safety of monoclonal antibodies including mepolizumab (anti-IL-5), reslizumab (anti-IL-5), QAX576 (anti-IL-13), omalizumab (anti-immunoglobulin-E), and infliximab (anti-TNF-α) in treatment of EoE. Our review indicates that although the use of monoclonal antibodies for EoE treatment is safe with limited and reversible adverse events, however, it is not yet possible to reach a final verdict on the efficacy of mAbs in EoE. Future well-designed studies are needed to clarify the exact role of mAbs in EoE.