Dihydrotanshinone I (DHT), a lipophilic compound extracted from Salvia miltiorrhiza, has cardiovascular protective effects, but the underlying molecular mechanisms of action have rarely been reported. Based on this, whether DHT affects cholesterol metabolism by regulating LDLR is investigated in this work. The results revealed that DHT can increase LDLR expression and promote LDL uptake by HepG2 cells. Meanwhile, DHT stabilizes LDLR mRNA expression by activating the epidermal growth factor receptor/extracellular signal-regulated kinase 1/2 (EGFR/erk1/2) signaling pathway. In addition, DHT inhibits the expression of the proprotein convertase subtilisin/kexin type 9 (PCSK9) by down-regulating the liver nuclear transcription factor 1 A (HNF1A) and up-regulating the forkhead box O3 (FOXO3). All of these indicate that DHT increases LDLR expression at the post-transcriptional and post-translational levels thereby promoting LDL-C metabolism. The potential mechanism of DHT to improve lipid metabolism has been revealed as a promising drug against AS.