To utilize the unique scaffold of a natural product indirubin, we herein adopted the strategy of combined pharmacophores to design and synthesize a series of novel indirubin derivatives as dual inhibitors against cyclin-dependent kinase (CDK) and histone deacetylase (HDAC). Among them, the lead compound <b>8b</b> with remarkable CDK2/4/6 and HDAC6 inhibitory activity of IC<sub>50</sub> = 60.9 ± 2.9, 276 ± 22.3, 27.2 ± 4.2, and 128.6 ± 0.4 nM, respectively, can efficiently induce apoptosis and S-phase arrest in several cancer cell lines. In particular, compound <b>8b</b> can prevent the proliferation of a non-small-cell lung cancer cell line (A549) through the Mcl-1/XIAP/PARP axis, in agreement with the unique modes of action of the combined agents of HDAC inhibitors and CDK inhibitors. In an A549 xerograph model, compound <b>8b</b> showed significant antitumor efficacy correlated with its dual inhibition. Our data demonstrated that compound <b>8b</b> as a single agent could be a promising drug candidate for cancer therapy in combination with CDK and HDAC inhibitors.