Chronic Lymphocytic Leukemia is a prevalent form of adult leukemia characterized by a heterogeneous clinical course and variable responses to therapy. The p53 protein, often dubbed "the guardian of the genome," plays a pivotal role in cellular responses to DNA damage, including cell cycle arrest, DNA repair, and apoptosis. Mutations in the TP53 gene, which encodes the p53 protein, or alterations in the p53 pathway, are of particular interest in Chronic Lymphocytic Leukemia due to their association with treatment resistance, aggressive disease progression, and poor prognosis. This article synthesizes recent research on the role of p53 in Chronic Lymphocytic Leukemia, emphasizing its impact on disease biology, therapeutic resistance, and clinical outcomes. Studies reveal that p53 mutations not only contribute to chemotherapy resistance but also delineate a subset of patients with significantly worse prognoses. The aberrant expression of p53-regulated non-coding RNAs and alterations in p53 signaling pathways further illustrate the complex role of p53 in Chronic Lymphocytic Leukemia pathogenesis and response to treatment. Furthermore, the interaction between p53 and other cellular pathways, such as Notch signaling, presents new opportunities for targeted therapeutic strategies. These insights underscore the critical role of p53 in Chronic Lymphocytic Leukemia and highlight the need for novel approaches to overcome p53-mediated resistance mechanisms, offering a beacon of hope for improving patient outcomes in this challenging disease.