The renin–angiotensin–aldosterone system has gained attention due to its role as a mediator of liver fibrosis and hepatic stellate cell (HSC) activation. Meanwhile, the natriuretic peptide (NP) system, including atrial NP (ANP) and C-type NP (CNP), is a counter-regulatory hormone regulated by neprilysin. Although the combination of an angiotensin receptor and a neprilysin inhibitor (sacubitril/valsartan: SAC/VAL) has shown clinical efficacy in patients with heart failure, its potential effects on hepatic fibrosis have not been clarified. This study assessed the effects of SAC/VAL in carbon tetrachloride (CCl4)-induced murine liver fibrosis as well as the in vitro phenotypes of HSCs. Treatment with SAC and VAL markedly attenuated CCl4-induced liver fibrosis while reducing α-SMA+-HSC expansion and decreasing hepatic hydroxyproline and mRNA levels of pro-fibrogenic markers. Treatment with SAC increased plasma ANP and CNP levels in CCl4-treated mice, and ANP effectively suppressed cell proliferation and TGF-β-stimulatedMMP2andTIMP2expression in LX-2 cells by activating guanylate cyclase-A/cGMP/protein kinase G signaling. Meanwhile, CNP did not affect the pro-fibrogenic activity of LX-2 cells. Moreover, VAL directly inhibited angiotensin II (AT-II)-stimulated cell proliferation and the expression ofTIMP1andCTGFthrough the blockade of the AT-II type 1 receptor/protein kinase C pathway. Collectively, SAC/VAL may be a novel therapeutic treatment for liver fibrosis.