AbstractInhibiting energy metabolism of cancer cells is an effective way to treat cancer but remains a great challenge. Herein, electrostimulation (ES) is applied to effectively suppress energy metabolism of cancer cells to induce rapid cell death, and deeply reveal the underlying mechanisms at the molecular and nanomechanical levels by combined use of fluorescence imaging and atomic force microscopy. Cancer cells are found significantly less tolerant to ES than normal cells; and ES causes “domino effect” to induce mitochondrial dysfunction to impede electron transport chain (ETC) and tricarboxylic acid (TCA) cycle pathways, leading to fatal energy‐supply crisis and death of cancer cells. From the perspective of cell mechanics, the Young's modulus decreases and cytoskeleton destruction of MCF‐7 cell membranes caused by F‐actin depolymerization occurs, along with down‐regulation and sporadic distribution of glucose transporter 1 (GLUT1) after ES. Such a double whammy renders ES highly effective and promising for potential clinical cancer treatments.