Aberrant activation of fibroblast growth factor receptor 2 (FGFR2) is a key oncogenic driver in multiple cancers, making it a compelling target for therapeutic intervention. This study aimed to explore marine high-salinity environments as underexplored reservoirs of microorganisms capable of producing FGFR2-targeting inhibitors. Eleven halophilic fungal strains belonging to four genera were isolated from the Beibu Gulf salt fields and identified through ITS rDNA sequencing. A targeted screening strategy employing an isogenic cell pair model—MDA-MB-231 wild-type versus FGFR2 S252W-overexpressing cells—coupled with an in vitro FGFR2 kinase inhibition assay, was used to evaluate fungal secondary metabolites. Notably, the extract from the marine-derived halophilic fungus Epicoccum sorghinum (strain GXIMD02001) demonstrated potent and highly selective anti-proliferative activity against FGFR2-overexpressing cells (IC₅₀ = 11.02 μg/mL), with markedly reduced effects on FGFR2-negative controls. Mechanistic studies confirmed that the active component acts as a direct and efficient FGFR2 kinase inhibitor, exhibiting 91.5% inhibition at 1 mg/mL, suggestive of ATP-competitive binding. Two additional strains (GXIMD02004 and GXIMD02009) showed broad-spectrum cytotoxicity. This work represents the first report of a marine halophilic fungus producing a selective FGFR2 inhibitor, underscoring the potential of extreme saline environments as prolific sources of novel kinase-targeting chemotypes. Our findings establish a foundation for the subsequent isolation and structural elucidation of a new FGFR2 lead compound from this unique microbial resource.