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Simple Summary: The dysregulation of ACSL3 and ACSL4, which belong to the long-chain fatty acyl CoA synthetase family (ACSLs), affects the behavior of various cancer cells. This review presents their distinct roles in ferroptosis and a summary of the double-edged effects of different cancers. Ferroptosis is a unique type of regulated cell death process which is caused by lipid peroxidation. Targeting the molecular mechanisms of ACSL3 and ACSL4 may provide more therapies for cancer treatments. The long-chain fatty acyl CoA synthetase (ACSLs) family of enzymes contributes significantly to lipid metabolism and produces acyl-coenzyme A by catalyzing fatty acid oxidation. The dysregulation of ACSL3 and ACSL4, which belong to the five isoforms of ACSLs, plays a key role in cancer initiation, development, metastasis, and tumor immunity and may provide several possible therapeutic strategies. Moreover, ACSL3 and ACSL4 are crucial for ferroptosis, a non-apoptotic cell death triggered by the accumulation of membrane lipid peroxides due to iron overload. Here, we present a summary of the current knowledge on ACSL3 and ACSL4 and their functions in various cancers. Research on the molecular mechanisms involved in the regulation of ferroptosis is critical to developing targeted therapies for cancer. [ABSTRACT FROM AUTHOR]