The levels of lipids in our bodies are regulated through regulatory proteins known as sterol regulatory element binding proteins (SREBPs). Dietary triglycerides are transported from the liver and intestine to body tissues by the microsomal triglyceride transfer protein (MTP). The role of the dysregulation of lipid components in metabolic diseases and cancer is reviewed herein. The current survey provides a comprehensive overview of published data spanning from 1997 to 2023, sourced from Scopus, Google Scholar, PubMed, Web of Science, and ScienceDirect, concerning dyslipidemia and the downregulation of SREBP-1, SREBP-2, and MTP gene expression by natural products. Natural products, mainly phenolic compounds such as hesperidin, luteolin, xanthohumol, silymarin, curcumin, and quercetin, triterpenes such as betulin, in addition to alkaloids as berberine, and fatty acids like oleic acid and α-linolenic acid were found to downregulate SREBP-1 and SERBP-2. Taxifolin, piperine, and ellagic acid inhibited MTP gene expression. Natural products regulating triglycerides and cholesterol gene expression could be key lead drugs to new medicines used to treat hyperlipidemia, hypercholesteremia, liver cancer, breast cancer, and metabolic disorders.