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Co-cultivation of isopod-associated fungi Herpotrichiasp. SF09 and Trametes versicolorSF09A led to the reciprocal induction of thirteen new compounds (1–7and 9–13) with diverse architectures. Importantly, compounds 1and 2are rare fungal sesquiterpene-saccharide hybrids incorporating a xylopyranose moiety, compound (±)-3represents the first example of a natural linear sesquiterpene racemate, and compound 7is a rare α-pyrone derivative with a xylopyranose motif. Their structures were elucidated by analysis of NMR and mass spectrometry data, and their absolute configurations were determined by Mosher’s method, microscale derivatization, and single-crystal X-ray diffraction, as well as ECD calculations. All the isolated compounds ameliorated MPP+-induced oxidative damage in PC12 cells in a dose-dependent fashion. Among them, compounds 5and 15showed significant protective action against neuronal injury by MPP+at 5 μM. Meanwhile, transcriptome sequencing was performed to evaluate the molecular mechanism of the neuroprotective activity for compound 5. Results indicated that compound 5might mitigate MPP+-induced neuronal injury through the regulation of multiple signaling pathways, including the PI3K-Akt and MAPK pathways. Our findings suggested that compound 5could be a promising neuroprotective agent for the treatment of Parkinson’s disease.