A series of new D‐ring ethisterones substituted with 1,4‐1,2,3‐triazoles were obtained in a facile manner via click chemistry reactions. The new compounds were characterized by multinuclear NMR spectroscopy, mass spectrometry, IR and unequivocally by single crystal X‐ray diffraction studies for compound 1. The cytotoxic activity of these derivatives was tested against a series of human cancer cell lines including human glioblastoma (U‐251), human prostatic adenocarcinoma (PC‐3), human colorectal adenocarcinoma (HCT‐15), human mammary adenocarcinoma (MCF‐7), human chronic myelogenous leukemia (K562), and human lung adenocarcinoma (SKLU‐1). Derivatives (3, X=Cl) and (5, X=I) showed promising cytotoxicity activities for leukemia adenocarcinoma (K562) and lung adenocarcinoma (SKLU). CI50% of K562: 11.72±0.9 μM (3) and 24.50±1.0 μM (5). CI50% of SKLU: 14.9±0.8 μM (3) and 46.0±2.8 μM (5). In addition, DNA docking simulations showed that all compounds interact with DNA through crosslink instrastrand p‐alkyl‐like interactions.