Diabetes mellitus (DM) is increasing rapidly worldwide, and diabetic cardiomyopathy (DCM) has become a leading cause of death in diabetic patients. Therefore, effective strategies for the prevention and treatment of DCM are urgently needed. Ferroptosis, a form of regulated cell death, has been implicated in the pathogenesis of DCM. This study integrated network pharmacology, data mining, molecular docking, molecular dynamics simulations, and in vitro experiments to investigate whether baicalein inhibits high glucose and sodium palmitate (HG + PA)-induced ferroptosis in cardiomyocytes and to elucidate the underlying mechanisms. Baicalein significantly improved the viability of H9c2 and AC16 cells, reduced cell death, and decreased LDH release under HG + PA conditions. Network pharmacology predicted that the protective effects of baicalein against HG + PA-induced cardiomyocyte injury were associated with ferroptosis regulation. Transcriptomic data mining further identified ferroptosis-related pathway enrichment in complementary in vitro and diabetic rat cardiac datasets. Molecular docking predicted favorable binding poses of baicalein with Nrf2, SLC7A11, and GPX4, while molecular dynamics simulations suggested general stability of the modeled complexes. In vitro experiments further confirmed ferroptosis involvement, as the ferroptosis inhibitor Ferrostatin-1 (Fer-1) reversed the HG + PA-induced decline in cell viability. Conversely, the ferroptosis inducer Erastin diminished cell survival and antagonized the protection conferred by baicalein, indicating that baicalein acts by inhibiting ferroptosis. Baicalein reduced lipid peroxidation, MDA and Fe2+ levels, and the mRNA expression of ACSL4 and PTGS2, while restoring the GSH/GSSG ratio and the protein expression of Nrf2, SLC7A11, and GPX4. These protective effects were partially reversed by the Nrf2 inhibitor ML385. In conclusion, baicalein protects cardiomyocytes from HG + PA-induced injury by activating the Nrf2/SLC7A11/GPX4 signaling pathway and inhibiting ferroptosis.