The effect of para (p)-cresol, an essential oil component, on calcium ion (Ca) signaling in human glioblastoma is unknown. The present study aimed to investigate how p-cresol influences intracellular Ca levels ([Ca]) and viability in DBTRG-05MG human glioblastoma cells. Cells were treated with p-cresol to assess its impact on cell viability and [Ca]. Cell viability was evaluated using a WST-1 assay. [Ca] was measured using a fluorescence-based Ca indicator. Cells were loaded with the Ca-sensitive dye (fura-2), and fluorescence intensity was recorded before and after p-cresol treatment to determine changes in [Ca]. p-Cresol induced concentration-dependent increases in [Ca] between 50 and 150 µM. At 50-250 µM, p-cresol triggered cell death; this effect was reversed by pretreating the cells with the Ca chelator BAPTA-AM. The removal of extracellular Ca inhibited Ca entry. p-Cresol-induced Ca influx was confirmed by Mn-induced quenching of fura-2 fluorescence. Store-operated Ca channel modulators SKF96365 and 2-aminoethoxydiphenyl borate and the protein kinase C inhibitor GF109203X inhibited p-cresol-induced Ca entry, but voltage-gated Ca channel blocker nifedipine did not. Treatment with the endoplasmic reticulum Ca pump inhibitor thapsigargin in Ca-free medium inhibited p-cresol-induced [Ca] rises; conversely, treatment with p-cresol decreased thapsigargin-induced [Ca] rises. Furthermore, phospholipase C (PLC) inhibition with U73122 abolished p-cresol-induced [Ca] rises. In DBTRG-05MG cells, p-cresol triggered Ca-associated cell death. The process involved the entry of Ca through PKC-regulated store-operated Ca channels and release of Ca from the endoplasmic reticulum, which depends on PLC. Additionally, BAPTA-AM, which has Ca-chelating properties, may be a promising compound in preventing p-cresol-induced cytotoxicity, a potential breakthrough in neurotoxic research in glioblastoma cell model.