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Free fatty acids (FFAs) and fatty acid synthesis (FAS) activity have significantly contributed to disease states such as insulin resistance, obesity, type 2 diabetes, myocardial infarction, blood pressure, and several types of cancer. Currently, several treatment options are available for patients with these conditions. Due to safety concerns, adverse effects, limited efficacy, and low tolerability associated with many medications, the identification of novel agents with less toxicity and a more favorable outcome is warranted. Curcumin is a phenolic compound derived from the turmeric plant with various biological activities, including anticarcinogenic, antioxidant, antiinflammatory, and hypolipidemic properties. PubMed, Scopus, and Web of Science were searched up to February 2020 for studies that demonstrated the efficacy and mechanisms of curcumin action on FFAs, FAS, and β-oxidation activity, as well as the desaturation system. Most of the evidence is in-vivo and in-vitro studies that demonstrate that curcumin possesses regulatory properties on FFAs levels through its effects on FAS and β-oxidation activity as well as desaturation system, which could improve insulin resistance, obesity, and other FFAs-related disorders. The present study provides a review of the existing in-vitro, in-vivo, and clinical evidence on the effect of curcumin on FFAs and FAS activity, β-oxidation, and desaturation system.