Sakuranetin is a plant-natural product, which has increasingly been utilized in cosmetic and pharmaceutical industries for its extensive anti-inflammatory, anti-tumor, and immunomodulatory effects. Sakuranetin was mostly produced via extraction technology from plants, which is limited to natural conditions and biomass supply. In this study, a novel strategy to produce sakuranetin via de novo synthesis from glucose by engineering S. cerevisiae was introduced . After a series of heterogenous genes integration, a biosynthetic pathway of sakuranetin from glucose was successfully constructed in S. cerevisiae which sakuranetin yield reached only 4.28 mg/L. Then, a multi-module metabolic engineering strategy was applied for improving sakuranetin yield in S. cerevisiae: (1) adjusting the copy number of sakuranetin synthesis genes; (2) removing the rate-limiting factor of aromatic amino pathway and optimizing the synthetic pathway of aromatic amino acids to enhance the supply of carbon flux for sakuranetin; (3) introducing acetyl-CoA carboxylase mutants ACC1S659A, S1157A, and knocking-out YPL062W to strengthen the supply of malonyl-CoA which is another synthetic precursor of sakuranetin. The resultant mutant S. cerevisiae exhibited a more than 10-fold increase of sakuranetin titer (50.62 mg/L) in shaking flasks. Furthermore, the sakuranetin titer increased to 158.65 mg/L in a 1-L bioreactor, which is the highest sakuranetin titer among all publications reported yield of the engineered microbial cell.