A new series of 6-arylaminoflavones was synthesized via the Buchwald-Hartwig cross-coupling reaction, aiming to functionalize the flavone core efficiently. Reaction optimization revealed that Pd₂(dba)₃/XantPhos with Cs₂CO₃ in toluene provided the best yields, with isolated yields ranging from 8% to 95%, depending on the arylamine structure. Steric hindrance and electron-withdrawing groups at the arylamine ring negatively impacted the reaction. Cytotoxicity assays indicated that specific substituents at the 6-position influenced biological activity, with trifluoromethyl- (13c) and chlorine-containing (13g) derivatives showing higher selectivity towards prostate cancer cells (PC3). These findings provide insights into the structure-activity relationship of 6-arylaminoflavones while contributing to the development of synthetic methodologies for functionalized flavones.