A series of 18 novelN‐Mannich bases derived from 5‐adamantyl‐1,2,4‐triazole‐3‐thione was synthesized and characterized usingNMRspectroscopy and X‐ray diffraction technique. All derivatives were evaluated for their anticancer potential against four human cancer cell lines. Several tested compounds exerted good cytotoxic activities on K562 andHL‐60 cell lines, along with pronounced selectivity, showing lower cytotoxicity against normal fibroblastsMRC‐5 compared to cancer cells. The effects of compounds5b,5e,and5jon the cell cycle were investigated by flow cytometric analysis. It was found that these compounds cause the accumulation of cells in the subG1 and G1 phases of the cell cycle and induce caspase‐dependent apoptosis, while the anti‐angiogenic effects of5b,5e,and5jhave been confirmed inEA.hy926 cells using a tube formation assay. Further, the interaction of Bax protein with compound5bwas investigated by means of molecular modeling, applying the combined molecular docking/molecular dynamics approach.