Diabetic cardiomyopathy (DCM), a critical complication of type 2 diabetes mellitus (T2DM), is marked by metabolic dysfunction, oxidative stress, and chronic inflammation, ultimately progressing to heart failure. This study investigated the synergistic therapeutic potential of Hippophae rhamnoides L. (sea buckthorn, SBU) extract and metformin in a mouse model of T2DM-induced DCM. T2DM was induced using a 45% high-fat-AGEs-enriched diet, followed by treatment with SBU, metformin, or their combination. Treatment effects were monitored through bioinformatic analysis, chemoinformatic prediction, behavioral testing, biochemical assays, histopathological evaluations and gene expression profiles. Based on bioinformatic analysis, we identified key hub genes involved in the diabetic cardiomyopathy including SERPINE1, NRG1, MYH11, PTH, NR4A2, NRF2, PGC1α, GPX4, ATF1, ASCL2, NOX1, NLRP3, CCK8, COX2, CCL2, PTGS2, EGFR, and oncostatin, which are pivotal in modulating the ferroptosis pathway. Furthermore, the expression of long non-coding RNAs (lncRNAs) NEAT1 and MALAT1, critical regulators of inflammation and cell death, was effectively downregulated, correlating with decreased levels of the pro-inflammatory marker oncostatin. The combined therapy significantly improved glucose regulation, reduced systemic inflammation and protected the heart from oxidative damage. Histopathological analysis revealed notable reductions in cardiac necrosis and fibrosis. Particularly, the combination therapy of SBU and metformin demonstrated a synergistic effect, surpassing the benefits of individual treatments in preventing cardiac damage. These findings highlight the potential of integrating SBU with metformin as a novel therapeutic strategy for managing DCM by targeting both metabolic and ferroptosis-related pathways. This dual intervention opens promising avenues for future clinical applications in diabetic heart disease management, offering a comprehensive approach to mitigating the progression of DCM.