Liver fibrosis is a major health concern worldwide. Inhibitors of Signal Transducer and Activator of Transcription 3 (STAT3) have been reported to attenuate experimental liver fibrosis. Therefore, the aim of this study was to investigate the potential ameliorative effect of cucurbitacin-B (Cucu-B) against CCl4-induced liver fibrosis in mice. Treatment with Cucu-B (5 mg/kg) preserved hepatocellular membrane integrity and amended the metabolic function as indicated by preventing the rise of serum liver function markers. This was confirmed histologically. CCl4-induced oxidative stress was improved by Cucu-B treatment (1 and 5 mg/kg). Furthermore, Cucu-B treatment ameliorated the fibrotic state as evidenced by inhibiting the rise of hydroxyproline liver content and mitigating the overexpressions of collagen-1α, α-smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-β) as well as the downexpression of matrix metalloproteinase-2 (MMP-2) mRNA. Importantly, STAT3 activity was inhibited by Cucu-B as confirmed by decreased phosphorylation of STAT3 without changing total STAT3 expression. This was substantiated by the reduced Bcl-2 together with increased Bax mRNA expressions with subsequent elevation of Bax/Bcl-2 ratio. In conclusion, Cucu-B hampers CCl4-induced liver fibrosis in mice. This can be attributed—at least partly—to inhibition of oxidative stress, inflammation and STAT3 signalling.