Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy, generally associated with high cure rates, though relapse remains a leading cause of mortality. TP53, located on chromosome 17p13, is a key tumor suppressor regulating cell cycle, apoptosis, and genomic stability. While TP53 mutations are rare at diagnosis, they are enriched in low-hypodiploid and relapsed ALL, conferring high-risk features and poor prognosis. We report two pediatric cases of TP53-mutated ALL with distinct clinical courses. The first case, a 10-year-old girl, presented with fever, gum bleeding, and cervical lymphadenopathy; bone marrow evaluation revealed precursor B-cell ALL with low-hypodiploid and a TP53 exon 7 missense mutation (c.743G＞A; p.Arg248Gln). She received BFM 2022 induction therapy, achieving morphological remission but remaining MRD-positive (1.5%), and attained MRD negativity (MRD＜0.01%) following high-risk consolidation, with haploidentical HSCT planned. The second case, a 12-year-old boy with late B-ALL relapse four years after initial remission, exhibited low-hypodiploid and a TP53 exon 4 missense mutation (c.370T＞G; p.Cys124Gly). Treatment with inotuzumab ozogamicin plus mini-HyperCVAD induced complete morphological and molecular remission (MRD＜0.01%), and he remains in sustained remission while awaiting haploidentical HSCT. TP53-mutated ALL represents a rare and aggressive subtype associated with high relapse rates and chemoresistance. Early molecular detection, incorporation of targeted immunotherapies, and timely allogeneic transplantation are essential strategies for improving outcomes in this high-risk group.