Background: Secondary acute myeloid leukemia (s-AML) is a subtype of acute myeloid leukemia AML that arises in the bone marrow and primarily affects white blood cells. It is associated with prior exposure to cytotoxic agents, including chemotherapy and radiotherapy. The risk of the disease increases with age and treatment intensity. Although s-AML represents 25–30% of all AML cases, its occurrence following radiotherapy is relatively rare. Diagnosis is confirmed via bone marrow biopsy, with differential diagnoses including other leukemias, lymphomas, and myelodysplastic syndromes. Prognosis is generally poor. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains the most effective curative option, though elderly patients often have limited eligibility due to comorbidities and poor performance status. Case: Five years after treatment for stage IIA rectal cancer, including radiotherapy, chemotherapy, and surgery, a 77-year-old male smoker presented with fatigue, weight loss, progressive dyspnea, headache, dizziness, blurred vision, and melena. Physical examination revealed pallor, purpura, skin crusts, and pustules. Laboratory findings showed anemia, thrombocytopenia, and circulating blasts. Bone marrow biopsy confirmed lymphoid infiltration. He was diagnosed with secondary acute myeloid leukemia (s-AML), likely therapy-related. Despite receiving three cycles of azacitidine, he died of septic shock seven months later. Conclusion: This case presents a rare and multifactorial association between prior chemotherapy, radiation therapy, and the development of therapy-related acute myeloid leukemia (t-AML). It highlights the importance of long-term hematologic surveillance in cancer survivors, particularly those exposed to alkylating agents and radiation, given their increased risk for secondary hematologic malignancies.