Objective <p>Esophageal cancer is a common tumor with low five-year survival rate and limited effective treatment. [⁶⁸Ga]Ga-FAPI-46 PET imaging has been used in the diagnosis of malignant tumors. Fibroblast growth factor receptor (FGFR) inhibitors have achieved good efficacy in a variety of tumors and fibrotic diseases. This study aimed to examine whether [⁶⁸Ga]Ga-FAPI-46 PET can monitor and predict the efficacy of FGFR inhibitors in animal models of esophageal cancer.</p> Methods <p>Pathological tissue sections from nine patients were collected to investigate the expression of FGFR2 in human esophageal cancer. [⁶⁸Ga]Ga-FAPI-46 and [¹⁸F]FDG microPET imaging were performed and tumor sizes were measured in a mouse model of FGFR2-positive KYSE520 tumor before and after infigratinib treatment.</p> Results <p>Immunohistochemical assay indicated that 66.7% (6/9) of patients were FGFR2 positive. Before infigratinib treatment, there were high radioactive uptakes in the KYSE520 xenograft tumors in a mouse model during [⁶⁸Ga]Ga-FAPI-46 microPET imaging. At the early stage of treatment with infigratinib (4 days), we found that tumor radiouptake in the treated group decreased significantly (%ID/g-mean: pre-treatment, 7.027 ± 1.348; post-treatment, 2.666 ± 1.267; <i>p</i> &lt; 0.001, <i>n</i> = 6). Tumor sizes of the infigratinib-treated group were significantly smaller than the untreated group, which could confirm the efficacy and safety of infigratinib in an esophageal cancer model.</p> Conclusion <p>Potent FGFR inhibitor infigratinib exhibits good efficacy in the preclinical model of esophageal cancer, and [⁶⁸Ga]Ga-FAPI-46 PET imaging may become a promising indicator for therapeutic efficacy of FGFR inhibitor drugs.</p>