Fungal melanins have remarkable bioactivities, but their practical applications are limited, partly due to their hydrophobic nature. Melanin modification with amino acids was reported to improve their water solubility. This research aimed to extract, and modify the melanins from Calvatia craniiformis and Xylaria plebeja with arginine, and to evaluate their neuroprotective effects against Parkinsonian toxins. MTT assay showed that all melanins and melanin derivatives could protect SH-SY5Y neuroblastoma cells from 1 mM H2O2. Xylaria plebeja melanin and melanin derivative at 100 µg/mL increased the cell viability about 16.0% compared to the negative control, whereas C. craniiformis melanin and its modified form enhanced the cell viability by 18.4% and 8.3%, respectively and that of the positive control (20 µM resveratrol) was 35.5%. Regarding neuroprotective effects against MPTP, the positive control, C. craniiformis melanin, and modified melanin increased the cell viability with approximately 5.0%, but that of X. plebeja melanin and modified melanin were 13.0%. Both melanins and melanin derivatives from C. craniiformis and X. plebeja showed significant neuroprotective effects against H2O2. However, only X. plebeja melanin and modified melanin displayed significant neuroprotective effects against MPTP and therefore they would be potential materials for follow-up research in Parkinson's disease prevention.