This work researched the influence and mechanism of CD155 on hepatocellular carcinoma advancement. CD155 expression and its effect on survival of hepatocellular carcinoma patients were analyzed based on the GEPIA2 database. String software predicted the interacting between CD155 and CD96, which was further verified by co-immunoprecipitation experiment. The function of CD155 and CD96 on the proliferation, migration, and invasion of hepatocellular carcinoma cells (HCC) was explored by colony formation, wound healing, and transwell assays. To research the effect of CD155 and CD96 on ferroptosis, ferroptosis-related factors in HCC were investigated. CD155 and p53 were both silenced in HCC to explore whether CD155 regulates hepatocellular carcinoma progression by acting on p53. Xenograft tumor study was conducted to examine the impact of CD155 on the in vivo growth of HCC. It was discovered that, CD155 up-regulation predicted poor survival of hepatocellular carcinoma patients. CD155 could be interacted with CD96. The proliferation, migration, and invasion of HCC were heightened by CD155. However, ferroptosis was suppressed by CD155, as CD155 decreased p53 and iron but increased SLC7A11, GPX4 and GSH in HCC. In fact, CD96 silencing abolished these effects of CD155. The suppressed malignant behaviors and the enhanced ferroptosis in HCC induced by CD155 silencing were abrogated by p53 silencing. In vivo, CD155 silencing suppressed growth and enhanced ferroptosis of hepatocellular carcinoma, which were counteracted by p53 silencing. Thus, CD155 might facilitate hepatocellular carcinoma advancement through blocking the p53-mediated ferroptosis via interacting with CD96. CD155 might be a promising target for treating hepatocellular carcinoma. KEY MESSAGES: CD155 was up-regulated in hepatocellular carcinoma, predicting poor survival. CD155 protein could be interacted with CD96 protein. Proliferation and invasion of liver cancer cells were facilitated by CD155. Proliferation and invasion of liver cancer cells were decreased by CD96 loss. CD155 promoted liver cancer by suppressing p53-mediated ferroptosis via CD96.