Parkinson's disease (PD) is characterized by progressive degeneration of dopaminergic nigrostriatal neurons and reduction in striatal dopamine levels. Although there are few treatment options for PD such as Levodopa, they are used just to relieve and modify the symptoms. There are no therapies available for PD to slow down the degeneration process in the brain and recover the lost function. In this study, we used extracellular matrix (ECM) mimetic peptide amphiphile (PA) nanofibers as a potential therapeutic approach in a PD rat model. We demonstrated the effect of heparan sulfate mimetic and laminin mimetic PA nanofibers on reducing striatal injury and enhancing functional recovery after unilateral striatal injection of 6-hydroxydopamine (6-OHDA). The bioactive self-assembled PA nanofibers significantly reduced forelimb asymmetry, contralateral forelimb akinesia and d-amphetamine-induced rotational behavior in cylinder, stepping and rotation tests, respectively, in 6-OHDA-lesioned rats after 6 weeks. The behavioral improvement with PA nanofiber administration was associated with enhanced striatal dopamine and tyrosine hydroxylase content as well as reduced cleaved-Caspase-3 levels. Histological assessment also showed that PA nanofiber injection to the striatum resulted in better tissue integrity compared to control groups. In addition, PA nanofibers reduced the progressive cell loss in SH-SY5Y cells caused by 6-OHDA treatment. These data showed that the bioactive peptide nanofibers improve neurochemical and behavioral consequences of Parkinsonism in rats and provide a promising new strategy for treatment of PD.Biomimetic nanomaterials bearing natural bioactive signals which are derived from extracellular matrix components like laminin and heparan sulfates provide promising therapeutic strategies for regeneration of the nervous system. However, no research has been reported exploring the use of biomimetic materials against degeneration in Parkinson's disease. In this work, we investigated potential therapeutic effects of heparan sulfate and laminin mimetic PA nanofibers on reduction of striatal injury in experimental Parkinson's disease model. PA nanofibers enhanced functional recovery associated with enhanced striatal dopamine and tyrosine hydroxylase content as well as reduced cleaved-Caspase-3 levels. Overall, this study shows the improvement in consequences of Parkinsonism in rats and provides a new platform for treatment of Parkinson's disease.