Oxidative stress plays a significant role in the development and progression of various pathologies. In heart failure, it is associated with multiple risk factors, such as diabetes and metabolic syndrome. Heart disease in different stages can further be linked to disrupted and abnormal metabolism in cardiac cells. To address the crosstalk of aberrant metabolism and alterations of the myocardial redox state correlated with oxidative stress and heart failure, differentially treated human stem cell-derived cardiac organoids (cardioids) were subjected to parallel mass spectrometry-based redox metabolomic and quantitative proteomic analyses. The impact of glucose availability and oxygen levels on the redox environment could be shown by the adaptive abundance of antioxidative enzymes specific to increased glycolytic flux or mitochondrial activity. Cardioids displayed distinct changes in the expression of proteins involved in collagen synthesis and modification, stress-mediated extracellular matrix remodelling, lipid metabolism and ion transport, as previously observed in the tissue of failing hearts. Additionally, metabolic alterations in response to hypoxic signalling further illustrate the impact of local oxygen concentrations on cellular activity. Results additionally disclosed the embryonic metabolic phenotype of the cardioid model, elucidating the importance of utilizing cardiac in vitro models appropriate to their respective translational ability to drive pathomolecular research. Alternatives were explored to address limitations. Ultimately, the design and implementation of a maturation media for AC16 proliferating human cardiomyocytes were carried out. RT-qPCR analysis revealed an improved phenotype as per the increased expression of multiple cardiomyocyte-specific markers.