The cardiotoxic effects of doxorubicin (DOX) are a significant clinical challenge. This study explored the mechanisms underlying the cardioprotective effects of fluvoxamine (FLU) in DOX-induced cardiotoxicity. In vitro and in vivo models of DOX-induced cardiotoxicity were established using H9c2 cardiomyocytes and BALB/c mice, respectively. The cardioprotective effects of FLU were evaluated using echocardiography, electrocardiography, HE staining, myocardial injury indicators, immunohistochemical staining, immunofluorescence staining, and western blotting. Small interfering RNA (siRNA) targeting the sigma-1 receptor (Sig1R), the Sig1R inhibitor haloperidol (HALO), and the nuclear factor erythroid 2-related factor 2 inhibitor ML385 were used to verify the mechanism of FLU in H9c2 cells, and molecular docking was performed to compare the binding affinities of DOX and FLU to Sig1R. DOX treatment significantly decreased Sig1R expression, leading to cardiac dysfunction, endoplasmic reticulum stress, apoptosis, impaired autophagy, oxidative stress, and mitochondrial dysfunction. Treatment with FLU mitigated these effects. Molecular docking simulations revealed that FLU showed better binding affinity for Sig1R than DOX. Moreover, the beneficial effects of FLU in DOX-induced cardiotoxicity were reduced in the presence of HALO, ML385, or Sig1R siRNA. Our study indicates that FLU effectively reduces DOX-induced cardiotoxicity by activating Sig1R, highlighting its potential as a therapeutic agent against chemotherapy-induced cardiotoxicity.