We　report　herein　the　design,　synthesis,　and　in　vitro　anti-tumor　activities　of　a　series　of　1,2,3-triazole-tetraethylene　glycol　tethered　heteronuclear　bis-Schiff　base　derivatives　of　isatin.　Our　results　indicated　that　all　the　synthesized　bis-Schiff　bases　except　9e　showed　considerable　in　vitro　anticancer　activities　against　HepG2,　Hela,　HCT-116,　A549,　and　MCF-7　human　cancer　cell　lines　with　IC50　in　a　range　of　9.79–48.75 μM　and　were　more　potent　than　etoposide　against　Hela,　HCT-116,　and　A549　cell　lines.　In　particular,　the　most　potent　bis-Schiff　base　9g　(IC50:　9.79–29.64 μg/mL)　was　highly　active　against　the　five　cancer　cell　lines　tested,　could　act　as　a　lead　for　further　optimization.　©　2018　Wiley　Periodicals,　Inc.