A series of novel isatin–coumarin hybrids was designed, synthesized, and assessed for their in vitro antitumor activities against drug‐sensitive HepG2, Hela, A549, DU145 (prostatic cancer), SKOV3, and MCF‐7 as well as drug‐resistant MCF‐7/DOX (doxorubicin‐resistant MCF‐7) human cancer cell lines. Results revealed that the synthesized hybrids displayed considerable activities against the tested seven cancer cell lines.