Doxorubicin, a potent anticancer drug, has well known dose‐dependent cardiotoxic side effects. In particular, doxorubicin exposure disrupts protein expression and impacts multiple biochemical pathways through the generation of reactive oxide species and oxidative stress, which in turn leads to cardiomyopathy and congestive heart failure. Specific effects of doxorubicin exposure at the biochemical, cellular, and tissue levels, have been extensively studied. However, a systematic quantitative assessment of the relative significance of these effects on the separate subsystems of the heart, in the perspective of overall cardiac function, remains to be done. Gaining such an understanding of the mechanisms underlying heart failure is essential for the development of diagnoses and treatments.Computational modeling provides a unique platform for exploring cardiac function in silico and gaining insight into the interplay between its separate mechanistic contributions, within the context of doxorubicin cardiotoxicity. We therefore developed a multi‐scale computational modeling framework to simulate the heart contraction cycle. The model was designed to be sufficiently detailed to include the main known aspects of cardiac muscle behavior, while retaining enough simplicity to enable its parameterization using clinical and experimental data. This approach provides a “virtual workbench” for simulating cardiac function with maximal objectivity and faithfulness with regard to measurements derived from patients.The model parameters were constrained using available data (echocardiography, cuff pressure, biopsy‐based proteomics analyses) derived from either doxorubicin‐treated or “control” cohorts. The flexibility of the model allows the determination of the sensitivities of the main cardiac phenotypes to specific parameters, in both cohorts. We thus aimed to identify the predominant pathway for the onset of doxorubicin cardiotoxicity, as characterized by a substantial lowering of the left‐ventricular ejection fraction (LVEF).Our results suggest that a structural remodeling of the heart (e.g., a widening of the left‐ventricular diameter) contributes partially to the decrease in LVEF. Additional necessary contributions must include changes to the passive or active contractile properties of the heart tissue. By using available proteomics analyses derived from patient biopsies, we aim to discern quantitatively between these contributions, resulting from cumulative doxorubicin exposure.Support or Funding InformationThis study is supported and funded as part of the European Commission HeCaTos Project (Hepatic and Cardiax Toxicity Systems modeling), Proposal 602156‐2.