Background and Purpose: The profibrotic and proinflammatory effects induced by doxorubicin (DOX) are key processes in the development of serious heart damage. The lack of effective drugs and the unclear mechanisms of their side effects limit the clinical treatment of DOX-induced cardiac injury. This study aimed to explore the protective role of LCZ696 and the potential mechanism of Toll-like receptor 2 (TLR2) in doxorubicin-induced cardiac failure. Experimental Approach: DOX (5 mg/kg/week, 3 times) was used to establish a chronic cardiomyopathy mouse model. Heart function tests, pathology examinations and molecular biology analyses were used to explore the effects of LCZ696 and TLR2 deficiency. H9C2 cells were used to verify the protective role and mechanism of LCZ696 in vitro. Key Results: The EF% declined, and the LVIDd, pro-fibrosis marker levels and NF-κB pathway-related inflammatory response increased in the chronic cardiomyopathy group induced by DOX. LCZ696 treatment and TLR2 deficiency reversed this heart damage in vivo. In H9C2 cells, pretreatment with LCZ696 and TLR2 knockdown suppressed the DOX-induced high expression of profibrotic and proinflammatory markers. Moreover, DOX notably increased the TLR2-MyD88 interaction in H9C2 cells, which was inhibited by LCZ696 pretreatment. Conclusion and Implications: LCZ696 prevents DOX-induced cardiac dilation failure, fibrosis and inflammation by reducing the formation of TLR2-MyD88 complexes. LZC696 may be a potential effective drug to treat DOX-induced heart failure.