Medicinal plants, recognized as significant natural resources, have gained prominence in response to the increasing global demand for herbal medicines, necessitating the large-scale production of these plants and their derivatives. Medicinal plants are exposed to a variety of internal and external factors that interact to influence the biosynthesis and accumulation of secondary metabolites. With the rapid development of omics technologies such as genomics, transcriptomics, proteomics, and metabolomics, multi-omics technologies have become important tools for revealing the complexity and functionality of organisms. They are conducive to further uncovering the biological activities of secondary metabolites in medicinal plants and clarifying the molecular mechanisms underlying the production of secondary metabolites. Also, artificial intelligence (AI) technology accelerates the comprehensive utilization of high-dimensional datasets and offers transformative potential for multi-omics analysis. However, there is currently no systematic review summarizing the genomic mechanisms of secondary metabolite biosynthesis in medicinal plants. Safflower (Carthamus tinctorius L.) has rich and diverse bioactive flavonoids, among of which Hydroxysafflor yellow A (HSYA) is specific to safflower and emerging as a potential medication for treating a wide range of diseases. Hence, significant progress has been made in the study of safflower as an excellent example for the regulation of secondary metabolites in medicinal plants in recent years. Here, we review the progress on the understanding of the regulation of main secondary metabolites at the multi-omics level, and summarize the influence of various factors on their types and contents, with a particular focus on safflower flavonoids. This review aims to provide a comprehensive insight into the regulatory mechanisms of secondary metabolite biosynthesis from the perspective of genomics.