Semen Ziziphi Spinosae (SZS) is used to treat neurasthenia, insomnia, and anxiety in China. The extract from SZS contains many bioactive components, such as flavonoids, alkaloids, and terpenoids. Among these, the flavonoids are the main bioactive compounds that have been proven to be responsible for the sedative effects. In this study, a total of 13232 differentially expressed genes and 83 flavonoid metabolites were identified at three different growth and development stages (T1, T2, and T3) of SZS using transcriptomic and metabolomic. The main flavonoid metabolic components of SZS were catechin, L-epicatechin, (-)-epigallocatechin, (+)-gallocatechin, spinosin and its derivatives. A total of 53 unigenes encoding 15 enzymes were identified as candidate genes involved in flavonoid biosynthesis in SZS. Among, PAL, C4H, 4CL, CHS, CHI, FLS, FNS, ANS, ANR, LAR, and UFGT genes were all downregulated in T3 than in T1. The expression levels of these genes influence the accumulation of flavonoids in SZS. Our results should provide valuable information for flavonoid metabolites and candidate genes involved in flavonoid biosynthesis on SZS.