The acyl-CoA synthetase long-chain (ACSL) belongs to an enzyme encoded by a polygenic family. ACSL, located in the endoplasmic reticulum and outer mitochondrial membrane, can catalyze fatty acids to form acyl-CoA, participating in many physiological processes, such as fatty acid metabolism and membrane modification. The ACSL family plays different roles in the fatty acid metabolism of different cells, and its dysfunction can lead to conditions such as fatty liver, arteriosclerosis, and diabetes. As a major subtype of the ACSL family in the liver, ACSL family member 1 (ACSL1) is mainly involved in the maintenance of cholesterol stability, fatty acid activation, and bile acid metabolism. It is also associated with the development of certain liver diseases such as hepatocellular carcinoma and steatosis. This paper reviews differences in physiological functions and functional characteristics of ACSL family members. It also discusses the advances in studies on the role of ACSL1 in influencing lipid metabolism, regulating cellular iron death, and the development of related diseases such as liver fibrosis, hepatocellular carcinoma, cachexia, steatosis, thyroid cancer, and breast cancer.