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Sixteen new polyketides, ophicirsins A–P (1–16), including four novel carbon skeletons (5–9, 14, 15, and 16), were isolated from the extract of an endophytic fungus Ophiobolus cirsiiLZU-1509. The unique frameworks of ophicirsin N (14) and O (15) feature a different cyclic ether connected with an aromatic ring system. Ophicirsin P (16) is characterized by the unprecedented heterozygote of a polyketide and an alkaloid. The absolute stereochemistries of those polyketides were characterized via single-crystal X-ray diffraction analysis and the experimental and computational electric circular dichroism spectra comparison. Theoretical reaction pathways in the fermentation to generate different novel skeletons starting from acetyl CoA and malonyl CoA helped to assign their structures. Compounds 1–16appear almost nontoxic in HepG2 and HT-1080 tumor cells. Their antioxidant effects were further evaluated, and 15exhibits an excellent protection activity in hydrogen peroxide-stimulated oxidative damage in neuron-like PC12 cells via screening all compounds. Moreover, 15displays a greater ability to scavenge the 2,2-diphenyl-1-picrylhydrazyl free radicals than resveratrol. Taken together, these findings suggest that the novel polyketides could serve as potential antioxidant agents for neuroprotection.