Liver cancer remains a worldwide concern, with more than 1 million new cases expected by 2025. Hepatocellular carcinoma (HCC) is the most prevalent type of primary liver cancer, making up around 80% to 90% of all primary liver cancers, whereas the other categories include cholangiocarcinoma (10-20%) and angiosarcoma (1%). Herbal treasure contains a number of novel phytochemicals that can be employed both therapeutically and preventively to address a variety of liver-related abnormalities, including HCC. Aim: To look into the prospective activity of Trianthema portulacastrum as a folkloric plant against HCC. Methods and materials: The extract of T. portulacastrum was prepared using dimethyl sulfoxide (DMSO). The cytotoxic activity of T. portulacastrum DMSO extract on HepG2 cell lines was affirmed using the MTT assay when compared to normal cells. It was trialled in-vitro for HCC activity against MEK-1 using quantitative real-time polymerase chain reaction (qRT-PCR). Results: It showed promising inhibitory activity against MEK-1 gene expression without any detectable cytotoxic effects. It significantly blocked the Ras/Raf/MEK/ERK tumor proliferation signaling pathway and induced an apoptotic signaling pathway. Conclusion: The T. portulacastrum DMSO extract inhibited the HepG2 cells proliferation and showed anticancer activity against HCC.