Physical constraints like compression influence cancer cell invasion and transcriptional dynamics in various tumors. Liver cancer is characterized by the rapid proliferation of tumor cells within a densely packed tissue matrix, subjecting the cancer cells to crowding and compression. The highly dysregulated mechanical environment highlights the need to elucidate the broader impact of compression on liver cancer development and evolution. In this study, we investigated and described a unique adaptive response of liver cells to prolonged compression. Liver cells presented significant transcriptional changes due to compression, including the loss of liver-specific markers and enrichment of epithelial-to-mesenchymal transition genes. Compression elevated Rac1 activity, which promoted cellular protrusions and YAP nuclear translocation and maintained cell viability under mechanical stress. Furthermore, compression disrupted intracellular calcium signaling, leading to resistance to apoptosis. Counteracting the effects of compression by inhibiting Rac1 or manipulating intracellular calcium facilitated death of compression-adapted cells. This study highlights compression as a critical biophysical signal in the tissue microenvironment that can induce cell state transitions and disease-driving phenotypes in the liver.