A series of arylsulfonyl mono-indoles (10–15), bis-indoles (16–27), and tris-indoles (28–32) have been synthesized and evaluated for their cytotoxicity toward four human cancer cell lines including HuCCA-1 (cholangiocarcinoma), HepG2 (hepatocellular carcinoma), A-549 (lung carcinoma), and MOLT-3 (lymphoblastic leukemia). Most of the synthesized indoles displayed cytotoxicity against the MOLT-3 cell line except for analogs 16, 17, and 32. Significantly, the $$N$$ N -sulfonylphenolic bis-indole series (18–27) and the $$N$$ N -chlorobenzenesulfonyl tris-indole (30) showed higher antiproliferative activity against HepG2 cell than the reference drug, etoposide. Promisingly, the $$N$$ N -chlorobenzenesulfonyl bis-indole (20) and tris-indole (30) provided 3-fold and 2-fold stronger activity, respectively, against HepG2 cell than etoposide. Moreover, the phenolic bis-indole (20) was also shown to be the most potent cytotoxic agent against HuCCA-1 and A-549 cell lines with $$\text{ IC }_{50}$$ IC 50 values of 7.75 and $$8.74\, \upmu \text{ M }$$ 8.74 μ M , respectively. The tris-indole analogs 28, 29, and 31 also exhibited selectivity against MOLT-3 cell. The findings disclosed that $$N$$ N -arylsulfonyl bis-indoles-bearing phenolic groups are potentially interesting lead pharmacophores of anticancer agents that should be further investigated in more detail.