Doxorubicin (DOX) is a widely used antitumor drug; however, its use is limited by the risk of serious cardiotoxicity. Dehydroevodiamine (DHE) is a quinazoline alkaloid which has antiarrhythmic effects. The aim of this study was to investigate the protective effect of DHE on doxorubicin-induced cardiotoxicity (DIC) and its potential mechanism. Rat H9c2 cardiomyocytes were exposed to DOX for 24 h to establish a DOX-induced cardiomyocyte injury model. DHE and ErbB inhibitor AG1478 were used to treat H9c2 cells to investigate their effects. Cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) release assays were used to evaluate cell viability. Flow cytometry and caspase-3 activity assay were used to detect apoptosis. Western blot was used to detect the expression levels of apoptosis-related proteins and neuregulin-1 (NRG1)/ErbB pathway-related proteins. The levels of proinflammatory cytokines and markers of oxidative stress were also detected, respectively. Quantitative polymerase chain reaction (qPCR) was used to detect mRNA expression levels of hub genes. DHE enhanced cardiomyocyte viability and decreased LDH release in a concentration- and time-dependent manner. DHE also significantly inhibited DOX-induced cardiomyocyte apoptosis, inflammation, and oxidative stress. Bioinformatics analysis showed that the protective mechanism of DHE against DIC was related to ErbB signaling pathway. DOX treatment significantly reduced NRG1, p-ErbB2, and p-ErbB4 protein expression levels in cardiomyocytes, while DHE pretreatment reversed this effect. ErbB inhibitor AG1478 reversed the protective effect of DHE on cardiomyocytes. DHE protects cardiomyocytes against DOX by regulating NRG1/ErbB pathway. DHE may be a potential agent for the prevention and treatment of DIC.