Background: Eosinophilic esophagitis (EoE) is a chronic antigen‐mediated clinicopathologic disease of the esophagus characterized by an eosinophil‐predominant inflammatory infiltrate. A clinical hallmark is extensive tissue remodeling including basal zone hyperplasia, fibrosis, and angiogenesis. However, the cellular mechanisms responsible for these processes are not fully defined. We hypothesized that targeting granulocyte‐macrophage colony‐stimulating factor (GM‐CSF; an agonist cytokine linked with eosinophil survival and activation) would be protective in a preclinical model of EoE. Methods: Eosinophilic esophagitis‐like esophageal inflammation was induced in the L2‐IL5OXA EoE mouse model, and GM‐CSF production was assessed by mRNA and protein analyses. Granulocyte‐macrophage colony‐stimulating factor‐receptor‐alpha expression patterns were examined by flow cytometric and immunofluorescence analysis. L2‐IL5OXA EoE mice were treated with anti‐GM‐CSF neutralizing antibody or isotype control and assessed for histopathological indices of eosinophilia, epithelial hyperplasia, and angiogenesis by immunohistochemistry and RT‐PCR. Results: Significantly increased levels of esophageal GM‐CSF expression was detected in the L2‐IL5OXA mouse EoE model during active inflammation. Granulocyte‐macrophage colony‐stimulating factor‐receptor‐alpha was predominantly expressed on esophageal eosinophils during EoE, in addition to select cells within the lamina propria. Anti‐GM‐CSF neutralization in L2‐IL5OXA EoE mice resulted in a significant diminution of epithelial eosinophilia in addition to basal cell hyperplasia and vascular remodeling. This treatment response was independent of effects on esophageal eosinophil maturation or activation. Conclusion: Granulocyte‐macrophage colony‐stimulating factor is a potential therapeutic target to reduce esophageal eosinophilia and remodeling.