Skin hyperpigmentation is a type of difficult-to-treat disease that frequently results from the improper metabolism of facial pigment. The herb Forsythiae Fructus (FF) possesses whitening and freckle-removal properties. Its probable active components and anti-hyperpigmentation mechanism, however, are still unknown. In the current investigation, the active components were initially identified and screened by UHPLC-Q-Orbitrap HRMS/ MS employing B16 cell-specific extraction and plasma pharmaceutical chemistry, respectively. Subsequently, the component-target-disease network and protein-protein interaction (PPI) network of FF were built by using a network pharmacology approach. The probable targets and pathways were found using gene ontology (GO) and KEGG enrichment analysis. The essential elements and core genes causing illnesses were identified through molecular docking. Lastly, based on network analysis, cell experiments were carried out to further explore the efficacy of the main active ingredients in the treatment of abnormal melanosis. As a result, 37 ingredients were identified in FF extract, 22 compounds in the decoction had a specific affinity with B16 mouse melanoma cells, and a total of 10 prototype compounds and 11 metabolites were detected in rat plasma. Through in vitro and in vivo screening methods, 16 potential active ingredients were obtained, and 229 biological targets and 1515 disease-related targets were predicted by network pharmacology. In addition, in vitro cell experiments revealed that kaempferol, luteolin, and wogonin all exhibited inhibition of melanin production and tyrosinase activity. The proposed combination method of rapid screening of active ingredients in vivo and integrated network pharmacology in vitro could explore the therapeutic mechanism of FF against hyper-pigmentation, and provide a theoretical evidence for the development and utilization of FF.