Flavonoids are plant secondary metabolites, which are valuable natural products widely used in human health and nutrition due to its biochemical properties such as antiviral, antiobesity, and anticancer. The efficient production of pure flavonoid compounds through plant extraction or chemical production continues to be a major challenge for drug development. Hence, the microbial production of flavonoids has emerged as an interesting and commercially attractive approach. The emergence of systems metabolic engineering offers new perspectives on strain and process optimization. In this review, the strategies of systems metabolic engineering used to overcome these challenges are summarized, which will offer insights into overcoming the limitations and challenges of large-scale microbial production of these important pharmaceutical compounds.