Familial adenomatous polyposis (FAP), an autosomal dominant disorder that predisposes to colorectal cancer, remains an area of unmet clinical need. This study aimed to develop a novel STMN1-targeting therapy for FAP. Using patient-derived organoids from seven FAP families and RNA sequencing, we identified significant STMN1 upregulation in FAP tissues, correlating with poor prognosis. Through drug repurposing and pharmacophore-based virtual screening of the DrugBank database, we optimized the menadione scaffold to develop novel small-molecule inhibitors. JYL-6 emerged as a leading compound in primary screens using FAP organoids. In Apcmin/+ mice, JYL-6 potently suppressed STMN1 expression and phosphorylation, reduced intestinal polyp number and burden, extended survival, and demonstrated a favorable systemic safety profile. Our results nominate STMN1 as a promising therapeutic target in FAP and highlight JYL-6 as a candidate with substantial translational promise, offering a new strategic direction for FAP treatment.