Background: Brucine is an alkaloid derived from the natural plant seeds of Strychnos nux-vomica, also known as a medicinal herb, and broadly employed in Chinese medicine for liver cancer. Objectives: The main intention of these hypothesis anticancer effects of brucine on 7,12-dimethylbenz(a)anthracene (DMBA)-induced skin cancer in mouse model through phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) regulating signaling pathway via the suppressive effect on cell proliferation and apoptotic pathways in mouse model. Materials and Methods: Brucine action on DMBA-induced mouse skin body weight, tumor volume, histology, biochemical, molecular marker analysis using spectrophotometric, Western blotting, and real-time polymerase chain reaction analysis. Results: Brucine stifled the lipid peroxidation (TBARS), suggestively augmented the levels of antioxidants (superoxide dismutase, catalase, glutathione peroxidase, and glutathione), and brought back the status of xenobiotic enzymes (Cyt-p450, Cyt-b5, and glutathione S-transferases). In brucine administered since skin tissues presented the cell proliferative protein marker expression of PI3K, and AKT were downregulated compared to the DMBA-applied skin tumor tissues protein. Further, brucine has downregulated the proliferating cell nuclear antigen, cyclin-D1, and p53 expressions. In the apoptotic expression, markers such as Bcl-2, Bax, caspase-3, and caspase-9 were upregulated compared to the DMBA-induced skin cancer. From these data, we diseased and brucine potential to suppress the proliferative cell markers induces apoptotic expressions. Conclusion: The current search settled that administering brucine chemopreventive and chemotherapeutic effect means for the cancer management in clinical tactic.