A series of 3-methyl-2-phenyl-1<i>H</i>-indoles was prepared and investigated for antiproliferative activity on three human tumor cell lines, HeLa, A2780, and MSTO-211H, and some structure-activity relationships were drawn up. The GI<sub>50</sub> values of the most potent compounds (<b>32</b> and <b>33</b>) were lower than 5 μM in all tested cell lines. For the most biologically relevant derivatives, the effect on human DNA topoisomerase II relaxation activity was investigated, which highlighted the good correlation between the antiproliferative effect and topoisomerase II inhibition. The most potent derivative, <b>32</b>, was shown to induce the apoptosis pathway. The obtained results highlight 3-methyl-2-phenyl-1<i>H</i>-indole as a promising scaffold for further optimization of compounds with potent antiproliferative and antitopoisomerase II activities.