Background and Purpose: Doxorubicin (DOX) represents a highly effective anthracycline, whose clinical application is limited by cardiotoxicity. The mechanisms underlying Doxorubicin-induced toxic cardiomyopathy (DICM) involve electrophysiological remodeling with intracellular Na overload as a consequence of increased late I Na, and hyperactivation of CaMKIIδ. Increased [Na] i contributes to CaMKIIδ activation through Na-dependent Ca overload, and CaMKIIδ can further amplify late I Na. Experimental Approach: We tested whether pharmacological inhibition of the late I Na by Ranolazine (RAN, 10 µmol/L) or Empagliflozin (EMPA, 1 µmol/L) is sufficient to attenuate DOX-mediated hyperactivation of CaMKIIδ in isolated wildtype (WT) ventricular cardiomyocytes. The contribution of reciprocal CaMKII-dependent stimulation of late I Na was tested in transgenic S571A cardiomyocytes lacking the CaMKII-specific phosphorylation site S571A on Na V 1.5. Functional readouts were obtained using patch-clamp technique, as well as confocal and epifluorescence microscopy. Key Results: DOX acutely increased late I Na in WT cardiomyocytes by 2-fold, which was associated with redox- and phospho-dependent activation of CaMKIIδ. Hyperactivated CaMKIIδ led to acutely impaired Ca handling as a consequence of diastolic Ca loss from the sarcoplasmic reticulum (SR) mediated by phosphorylation of the RyR2 at the CaMKII-specific phosphorylation site serine-2814. Pharmacological inhibition of late I Na by EMPA or RAN, and genetic deletion of the CaMKII-specific phosphorylation-site ser-571 at Na V 1.5 prevented DOX-related stimulation of the late I Na and subsequent CaMKIIδ hyperactivation, which functionally preserved intracellular Ca handling. Conclusion and Implications: Inhibition of late I Na protects cardiomyocytes from pathologic CaMKIIδ hyperactivation and impaired Ca handling in the setting of acute DOX cardiotoxicity.