Hepatocellular carcinoma (HCC) is the most important case of liver cancer disease particularly in Egypt. On the other hand, autophagy plays critical role in cellular immune response in different disease including cancer. Notably autophagosome formation required different proteins interaction for initiation, elongation and maturation steps known as Atg proteins . Additionally, tumor suppressor gene including P53 gene play regulatory role in cells proliferation and cell division, down regulation of P53 gene leads to improvement of carcinogenic cells and enhancement of cell proliferation. Here we aim to investigate the possible connection between P53 gene expression and autophagic machinery on HCC upon treatment with some naturally occurring products using HepG2 cell lines. Our findings indicate that, treatment with Guava leafs and Guava flowers extraction increase the expression profile of P53 gene and reduce autophagosome formation indicated by LC3 gene expression. Conversely, the treatment of guava leafs and guava flower extraction on normal cell (normal melanocyte) stimulate autophagic machinery with neutral influence on P53 expression without any detectable cytotoxic effect. Collectively, the natural product from guava leafs and flowers regulate cell proliferation via inhibition of autophagosome formation associated with activation of p53 signaling pathway in HCC. These findings strongly indicate that the indicated nature products can be attractive candidates in therapeutically strategy for liver cancer development.