Background: Intrinsically disordered regions (IDRs) within proteins often act as pivotal linkage units for the interaction of functional domains. The p53 tumor suppressor protein contains intrinsically disordered N-terminal and C-terminal domains (NTD and CTD), playing crucial regulatory roles in cellular processes. Furthermore, experimental approaches have encountered challenges in elucidating the structural regulation by the IDRs. Methods: In this work, we employed microsecond-scale molecular dynamics simulations to explore the allosteric regulation mechanism of the p53 DNA binding domain (DBD) induced by the CTD and the DNA binding. Subsequently, we integrated dynamic cross-correlation analysis with binding free energy calculations to evaluate the interaction between the CTD and DNA. Results: The free energy landscapes (FELs) were utilized to identify the conformational ensemble of the p53 DBD. The FELs revealed that the CTD enhances the allosteric regulatory mechanisms. Conclusions: Firstly, the conformation of DBD changes on the S6-S7 loop and L1 upon DNA binding. Then the CTD directly interacts with DNA and further regulates the allosteric network (involving the S6-S7 loop, L1 loop, S4, S10, H1, and H3) to promote the binding of DBD to DNA. The allosteric mechanisms presented in this work will provide new insights into the functional mechanisms of the p53 CTD and inform the rational design of p53-targeted drugs.