Abstract: Intrahepatic cholangiocarcinoma (ICC), the second most common primary liver malignancy after hepatocellular carcinoma (HCC), has seen a dramatic rise in incidence in recent years without effective therapeutic drugs. Hu Qi San (HQS), an empirical formula developed by professor Qian Ying, a renowned traditional Chinese medicine expert, through years of clinical practice, has demonstrated clinical efficacy in chronic viral hepatitis and primary hepatocellular carcinoma. However, fundamental research on HQS for ICC remains uncleared. Thus, this study utilized a sgp19-KRas mouse model with typical ICC-like lesions and a QBC-939 cell model to evaluate the therapeutic effects of HQS on ICC in vitro and in vivo and elucidate its underlying mechanisms. First, crystal violet staining and EdU assays revealed that HQS significantly inhibited the proliferation and migration of QBC-939 cells (P < 0.05). Subsequently, sgp19-KRas mice were treated with daily oral administration of 20 g·kg^-1 HQS for three weeks. Results demonstrated that HQS effectively suppressed ICC growth and tumor cell proliferation in sgp19-KRas mice, while improving survival rates. Mechanistically, network pharmacology analysis predicted 303 overlapping targets between HQS's active components and ICC-related disease targets, with significant enrichment in the Hippo signaling pathway. The molecular docking results predicted that ononin, calycosin, gallic acid, and taxifolin in HQS can directly bind to Yes-associated protein (YAP). Experimental validation further demonstrated that these four components exhibit in vitro inhibitory effects on QBC-939 cells. Subsequent q-PCR and Western blot analyses of liver tissues from treated sgp19-KRas mice confirmed that HQS inhibited the transcription of YAP, downregulated YAP protein expression, and suppressed the transcription of YAP downstream genes, particularly those in the YAP-Notch pathway. In conclusion, this study demonstrates that HQS exhibits potential therapeutic effects on ICC, and its mechanism of action is closely associated with the YAP-Notch signaling pathway.