AbstractHepatocellular carcinoma (HCC) is recognized as the fifth most common cancer and the third most common cause of death in Asian population. Studies reported that HCC is relatively insensitive to radiotherapy (RT); thus, considering how to sensitize HCC to RT is worth to be elucidated. Epidermal growth factor receptor (EGFR)‐mediated signalling transduction plays the important role in regulating treatment efficacy of HCC. An active compound, 18beta‐glycyrrhetinic acid (18β‐GA), has been reported to own anti‐tumour effect. However, whether 18β‐GA possess RT sensitization ability in HCC remains unclear. Here, we used RNA data from TCGA‐LIHC (Liver hepatocellular carcinoma) to identify the role between EGFR/ERK/nuclear factor kappa B (NF‐κB) signalling and RT by radiosensitivity index (RSI) analysis. We suggested that patients with activated NF‐κB signalling may show resistance to RT treatment, whereas combining 18β‐GA may reinforce RT efficacy in a Hep3B‐bearing animal model. 18β‐GA combined with RT showed superior tumour inhibition capacity as compared to monotherapy and even reached similar efficacy as erlotinib combined with RT. Treatment promotion of RT by 18β‐GA in HCC is not only through diminishing RT‐induced EGFR/ERK/NF‐κB signalling but also promoting RT‐induced apoptosis pathways. 18β‐GA may act as radiosensitizer through inactivating EGFR‐mediated HCC progression and inducing caspase‐dependent apoptosis signalling.