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We evaluated the neuroprotective effect of L-theanine in Parkinson's disease and the underlying mechanism focusing on WNT/β-catenin signaling mediated by the MAPK pathway. We treated MPTP-induced SH-SY5Y cells with various concentrations of L-theanine (50, 100, 200, and 500 μg/mL), and we also treated Parkinson's model mice with L-theanine. L-theanine treatment effectively reduced the immunohistochemical hallmarks of Parkinson's disease, particularly Lewy bodies and α-synuclein, and increased the number of tyrosine hydroxylase-positive cells. L-theanine also improved the motor dysfunction in MPTP-induced Parkinson's disease model mice as measured by the rotarod test. The levels of several pro-inflammatory mediators that are overexpressed in Parkinson's disease, namely TNF-α, IL-6, COX-2, and MAC-1, were reduced following L-theanine treatment, and the levels of the pro-apoptotic proteins Bcl-2, caspase-3, p53, and PARP-1 were significantly reduced. L-theanine regulated the oxidative stress-related factors SOD-1, GST, and NOX-4 by targeting several proteins related to WNT/β-catenin signaling, i.e., β-catenin, WNT-3a, WNT-5a, TCF1/TCF7, and LEF1, via the MAPK pathway (p -JNK, p -ERK, and p -p38). Our results indicate that L-theanine is neuroprotective and has anti-inflammatory effects that could be beneficial for treating Parkinson's disease. L-Theanine facilitated the neuroprotective effect by mediating the Wnt/b-catenin signaling pathways. L-theanine has activated both Wnt/β-catenin signaling and the MAPK signaling pathways, subsequently downregulating the pro-inflammation, apoptosis, and oxidative stress mediators and enhancing the motor function. [Display omitted] [ABSTRACT FROM AUTHOR]