The concept that mechanical cell competition may contribute to tumor cell expansion has been widely discussed. However, whether this process could occur during natural tumor progression, as well as its underlying mechanisms and clinical implications, remains largely unknown. In this study, we observed that self-seeded tumor cell lines of human oral cancer, SCC9- and SCC25-seeded cells, exhibited a mechanical competitive advantage, outcompeted neighboring cells, and became "winner" cells. Mechanical compression-induced calcium influx activates myosin II in "loser" cells, leading to apoptotic nuclear breakdown and subsequent clearance. N-cadherin/Rac1/PAK1/myosin light-chain kinase (MLCK)-controlled myosin II inactivation endows cells with resistance to mechanical stress and superior cellular flexibility, thus providing a cell competition advantage to self-seeded cells. The activation of the N-cadherin/Rac1/PAK1/MLCK/myosin II signaling axis is associated with drug resistance. Together, these results suggest that N-cadherin/Rac1/PAK1/MLCK signaling-induced myosin II inactivation enables tumor cells to acquire resistance to mechanical stress and a competitive advantage. Our study also provides insights into drug resistance from a stress-sensitivity perspective.