Cells reorganize their membrane biomechanical dynamics in response to environmental stimuli or inhibitors associated with their physiological/pathological processes, and disease therapeutics. To validate the biophysical dynamics during cell exposure to anti-cancer drugs, we investigate the nanoscale biological characterization in melanoma cells undergoing cisplatin treatment. Using atomic force microscopy, we demonstrate that the cellular morphology and membrane ultrastructure are altered after exposure to cisplatin. In contrast to their normal spindle-like shape, cisplatin causes cell deformation rendering cells flat and enlarged, which increases the cell area by 3-4 fold. Additionally, cisplatin decreases the topography height values for both the cytoplasmic and nuclear regions (by 40-80% and 60%, respectively). Furthermore, cisplatin increases the cytoplasmic root mean square roughness by 110-240% in correlation with the drug concentration and attenuates the nuclear RMS by 60%. Moreover, the cellular adhesion force was enhanced, while the Young's modulus elasticity was attenuated by ∼2 and ∼2.3 fold, respectively. F-actin phalloidin staining revealed that cisplatin enlarges the cell size through enhanced stress fiber formation and promotes cytoskeletal reorganization. Immunoblot analyses further revealed that the activities of focal adhesion proteins, such as FAK and c-Src, are upregulated by cisplatin through phosphorylation at tyrosine 397 and 530, respectively. Collectively, these results show that cisplatin-treated melanoma cells not only exhibit the upregulation of FAK-mediated signaling to enhance the cytoskeleton mechanical stretch, but also promote the cytoskeletal rearrangement resulting in 43% decrease in the cell modulus. These mechanisms thus promote the malignancy and invasiveness of the melanoma cells.