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 impacted the reaction outcomes. Cytotoxicity assays in different human cancer cell lines indicated that substitution patterns at both the arylamine and B-rings strongly impacted biological activity. In particular, compounds bearing a 3,4-dimethoxy substitution at the B-ring and a trifluoromethyl (13c) or chlorine (13g) group at the aniline moiety exhibited enhanced cytotoxicity. These findings provide insights into the structure–activity relationship of 6-arylaminoflavones while contributing to the development of synthetic methodologies for functionalized flavones.