Cardiac fibrosis plays a causal role in the development of heart failure, and anti-fibrotic therapy represents a promising strategy to mitigate heart failure. The purpose of this study was to investigate the effect of a new drug-liguzinediol on cardiac fibrosis of heart failure Male Sprague-Dawley rats (SD) rats and the underlying mechanisms. Liguzinediol was administered to rats that were injected with doxorubicin (Dox) for four weeks. Two weeks later, its effects on cardiac fibrosis were assessed by haematoxylin and eosin (HE) staining and Masson staining. The collagen content was determined by Elisa, and protein expression was detected by western blot in vitro and in vivo. Liguzinediol decreased cardiac muscle fiber break evidenced by HE staining and it significantly reduced cardiac fibrosis evidenced by Masson staining in DOX-treated rats. In addition, the hydroxyproline level and the ratio of type I/III collagens were also significantly decreased, and western blot assays showed that liguzinediol regulated the balance between matrix matalloproteinases (MMPs) and tissue inhibitor of metalloproteinase (TIMPs) to protect cardiac remodeling in vivo and in vitro. These data collectively indicated that liguzinediol could protect against cardiac fibrosis in rats. Liguzinediol could be exploited to be a promising candidate for cardiac fibrosis.