The administration of regular used in vitro dose (10 μM) in 3D and 2D cultures, as well as the dose–response analysis in 2D cultures showed Sorafenib and Regorafenib were increasingly effective in reducing cell proliferation, and inducing apoptosis in well-differentiated and expressing wild-type p53 in HCC cells. Here, TP53 is linked to hepatocellular carcinoma.