Acute myeloid leukemia (AML) is an aggressive hematologic malignancy characterized by the clonal expansion of primitive hematopoietic stem cells. Despite therapeutic advances, including chemotherapy, hypomethylating agents, and FLT3 inhibitors, resistance and relapse remain major clinical challenges. One of the contributors to chemoresistance in AML is the nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that regulates redox homeostasis and promotes cell survival under oxidative stress. Under normal conditions, Kelch-like ECH-associated protein 1 (KEAP1) inhibits Nrf2. In response to oxidative stress, KEAP1 becomes inactivated, allowing Nrf2 to be activated. Nrf2 is then transported to the nucleus, where it facilitates the transcription of genes that protect cells from oxidative stress. Although vital for protecting cells from oxidative damage, recent studies have also proved the dual role of Nrf2 in cancer progression. The persistent activation of Nrf2 is associated with many cancer types, including AML. This review provides a brief discussion of the molecular mechanisms by which Nrf2 contributes to therapy resistance in AML, with a focus on its regulation of miRNAs, HO-1 1upregulation, and metabolic reprogramming via the pentose phosphate pathway (PPP). We also summarize the pathways involved in Nrf2 activation in AML and the limitations of current treatments that trigger oxidative stress, thereby leading to Nrf2-driven resistance. For AML treatment, recent research has placed a greater emphasis on combination therapy approaches that include Nrf2 inhibitors, in addition to traditional chemotherapeutic medicines such as doxorubicin, or targeted therapies like the BCL-2 inhibitor venetoclax. This review also analyses these studies to determine whether a combination strategy would be an appropriate method for treating AML.