For the last three decades, metalloenzymes such as histone deacetylases (HDACs) and matrix metalloproteinases (MMPs) have been identified in promoting solid as well as hematological carcinogenesis. Histone deacetylase 8 (HDAC-8), a class I HDAC enzyme, may serve as ‘epigenetic player’ that affects in the regulation of transcription factors and alters the structure of chromosome associated with tumorigenesis. It is established that the influence of MMP-2 in invasion, metastasis and angiogenenic events of hematological malignancies may be suppressed by HDAC inhibitors through reversion-inducing-cysteine-rich protein with kazal motifs (RECK) protein. Therefore, the isoform-specific HDAC-8 and MMP-2 inhibitors may provide synergistic medicinal benefit in leukemia. However, a paucity of articles is available on dual acting HDAC-8/MMP-2 inhibitors. In this circumstance, a lot of works are still necessary to identify novel dual HDAC-8/MMP-2 inhibitors and this review will surely provide an initial idea regarding the utility of designing such type of dual inhibitors. Here, the importance of MMP-2 and HDAC-8 inhibition in hematological malignancies are focussed for the first time as per our knowledge along with the structure-activity relationships (SARs) of a handful of molecules, some of which were synthesised in-house, have been highlighted that will inspire more interactions between the medicinal chemistry and biology community to harness their expertise in design and discovery of the better acting dual inhibitors in future.