Abstract: Venetoclax, a BCL-2 inhibitor that induces apoptosis, is primarily employed to treat hematological malignancies and has been shown to substantially improve complete response (CR) in patients with acute myelogenous leukemia (AML). However, with the widespread clinical application of venetoclax, cases of acquired drug resistance have emerged. To address this issue, extensive research has been conducted to explore ferroptosis as an alternative programmed cell death pathway that reverses venetoclax resistance. This review discusses the potential mechanisms of acquired resistance to venetoclax in hematological malignancies, provides an overview of several crucial regulatory pathways associated with abnormal energy metabolism-induced ferroptosis in tumor cells, and summarizes various approaches to modulate energy metabolism in tumor cells to alter ferroptosis and potentially reverse acquired resistance to venetoclax, ultimately guiding the clinical application of venetoclax.