Abstract: Guided by molecular networking, HSQC-based DeepSAT, and SMART analyses, a chemical investigation of the coral-derived fungus Talaromyces sp. TJ403-AL05 led to the isolation and identification of taladipyrones A−I (1−9), a series of new α-pyrone dimers with four distinct skeletons. Among these, compounds 1 and 9 represented two unprecedented classes of rearranged α-pyrone dimers, and compounds 5−7 were the first talarolactone-type dimers obtained as racemates. Extensive spectroscopic analysis, quantum chemical calculations, and X-ray diffraction analysis were used to determine their structures, including each enantiomer of racemic compounds 5−8 after chiral HPLC resolution. In human cardiomyocytes (AC16), compounds 1−6 and 8−9 attenuated injury caused by 24 h cold ischemia (CI) at 40 µmol·L⁻¹. Moreover, compound 2 could improve CI-induced disruption of redox homeostasis via activation of the PI3K/AKT signaling pathway, representing the first fungal polyketide with such cardioprotective activity.