<p>Human Papillomavirus (HPV) types 16 and 18 are well-established causative agents in cervical cancer. However, the mechanism of malignant transformation remains unclear. Although epithelial-mesenchymal transition (EMT) is regulated by Ca²⁺ signaling, the functions of transient receptor potential canonical (TRPC) channel in cervical cancer have not been reported. Herein, employing multiple biological approaches, we first revealed that HPV16 and HPV18 infections significantly upregulated the expression of <i>TRPC3</i> that orchestrated Ras-MAPK and MEK-ERK pathways in the abnormal transformation of cervical epithelial cells. Our transcriptomic sequencing of HPV-infected cervical epithelial cells with depletion of <i>TRPC3</i> suggested the significant influence of <i>TRPC3</i> on genes involved in the process of epithelial-mesenchymal transition (EMT). Consistently, inhibition of <i>TRPC3</i> successfully suppressed HPV-triggered cell viability and EMT. Moreover, we found <i>TRPC3</i> maintained the viability of HPV - infected cells by suppressing excessive MAPK activation through regulating Ras GTPase - activating protein 4 (RASA4), which was validated by the detection of phosphorylated ERK1/2 (p-ERK1/2).These findings were further confirmed in the HPV-infected female BALB/c mice, highlighting <i>TRPC3</i> as a key hub in mediating transformation This study advances the knowledge about the Ca²⁺ signaling-related molecular mechanism underlying HPV-driven malignant transformation. Targeting <i>TRPC3</i> may have broader therapeutic implications.</p>