Over recent years, histone deacetylases (HDACs) have gained great interest as key epigenetic modulators involved in the regulation of several cellular processes, and their overexpression has been associated with the initiation and progression of different types of cancer. Several HDAC inhibitors have been approved for the treatment of different subtypes of blood malignancies; however, the majority of them show some limitations, including genotoxicity, mutagenicity, and undesirable adverse effects. One strategy that could be used to overcome such problems and improve drug delivery to selected cell types is the design of prodrugs. In the current study, a novel series of bioreductive nitroaromatic prodrugs for class I HDACs has been designed and synthesized based on different reported HDAC1, 2, and 3 inhibitors. The aminobenzamide part (ZBG) of the selected HDAC inhibitors was masked with different nitroarylmethyl alcohols through a carbamate linker. Such attachment should reduce the binding to the targeted HDACs, which could be explained by the weaker HDAC inhibitory activity of the newly synthesized prodrugs compared to the parent inhibitors. Furthermore, the biological activity of the newly synthesized prodrugs was evaluated against THP1 acute myeloid leukemia cells using a nitroreductase (NTR) prodrug system. This prodrug system catalyzes the reduction of the nitro group of different nitroaromatic substrates of cytotoxic amines to release the active inhibitor selectively in NTR-expressing cells. Cellular testing revealed that two 2-nitroimidazole-based prodrugs (5 and 6) were activated by the NTR prodrug system. Both compounds showed cellular effects almost in the range of the corresponding parent inhibitors. Compound 6 showed potent activity against the NTR-THP1 cell in the nanomolar range. In addition, it exhibited a moderate selectivity window. The in vitro prodrug activation by NTR was confirmed by LC-MS analysis, which showed the release of the parent inhibitor after incubation of the prodrug 6 with E. coli NTR. This work demonstrates that we successfully synthesized and evaluated a novel class I HDAC prodrug with good bioreductive properties, which can be used as a good starting point to enhance the selectivity and for further optimization. In addition, our model shows the potential to genetically engineer tumor cells with a bacterial nitroreductase for specific activation.