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A new and readily available pentafluorothiophenyl-substituted N-methyl-piperidone curcuminoid <b>1a</b> was prepared and investigated for its anti-proliferative, pro-apoptotic and cancer stem cell-differentiating activities against a panel of human tumor cell lines derived from various tumor entities. The compound <b>1a</b> was highly anti-proliferative and reached IC₅₀ values in the nanomolar concentration range. <b>1a</b> was superior to the known anti-tumorally active curcuminoid EF24 (<b>2</b>) and its known N-ethyl-piperidone analog <b>1b</b> in all tested tumor cell lines. Furthermore, <b>1a</b> induced a noticeable increase of intracellular reactive oxygen species in HT-29 colon adenocarcinoma cells, which possibly leads to a distinct increase in sub-G1 cells, as assessed by cell cycle analysis. A considerable activation of the executioner-caspases 3 and 7 as well as nuclei fragmentation, cell rounding, and membrane protrusions suggest the triggering of an apoptotic mechanism. Yet another effect was the re-organization of the actin cytoskeleton shown by the formation of stress fibers and actin aggregation. <b>1a</b> also caused cell death in the adherently cultured glioblastoma cell lines U251 and Mz54. We furthermore observed that <b>1a</b> strongly suppressed the stem cell properties of glioma stem-like cell lines including one primary line, highlighting the potential therapeutic relevance of this new compound.