Aim: Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. Transcription factor p53 induces cell cycle arrest and apoptosis in response to DNA damage and cellular stress, thereby playing a critical role in protecting cells from malignant transformation. The oncoproteins MDM2 and MDMX negatively regulate the activity and stability of the tumor suppressor protein p53, conferring tumor development and survival. Methods: In this work, we firstly explored the feasibility of antagonists targeting the p53-binding domains of MDM2 and MDMX as a potential method for HCC therapy via the survival rate analysis in The Cancer Genome Atlas. Moreover, we developed a novel stapling strategy for peptide drug design using the reaction between mercapto group and bromine to crosslink the side chains of the two Cys at (i, i+4) positions, and apply it to a series of peptides derived from a dodecameric peptide antagonist of both MDM2 and MDMX, termed p53-MDM2/MDMX inhibitor (PMI). Results: Notably, all of these stapled peptides can compete with p53 for MDM2 or MDMX binding as the similar affinityas PMI. More importantly, this stapling functionally rescued PMI that, on its own, failed to activate p53 because of its poor membrane permeability and susceptibility to proteolytic degradation. Conclusion: Taken together, this work not only illustrates that the restoration of p53 is a potentially feasible program for HCC therapy, but promises an important new tool for peptide drug discovery and development for a variety of human diseases.