In cardiomyocytes, a major decrease in the level of sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA) can severely impair systolic and diastolic functions. In mice with cardiomyocyte-specific conditional excision of the Serca2 gene (SERCA2 KO), end-stage heart failure developed between four and seven weeks after gene deletion combined with [Na⁺]_i elevation and intracellular acidosis. In this study, to investigate the underpinning changes in Ca²⁺ dynamics and metabolic homeostasis, we developed data-driven mathematical models of Ca²⁺ dynamics in the ventricular myocytes of the control, four-week, and seven-week SERCA2 knockout (KO) mice. The seven-week KO model showed that elevated [Na⁺]_i was due to increased Na⁺ influxes through the Na⁺/Ca²⁺ exchanger (NCX) and the Na⁺/H⁺ exchanger, with the latter exacerbated by intracellular acidosis. Furthermore, NCX upregulation in the seven-week KO model resulted in increased ATP consumption for ion transport. Na⁺ accumulation in the SERCA KO due to NCX upregulation and intracellular acidosis potentially play a role in the development of heart failure, by initiating a reinforcing cycle involving: a mismatch between ATP demand and supply; an increasingly compromised metabolism; a decreased pH_i; and, finally, an even greater [Na⁺]_i elevation.