Neurotrophins exert their physiological functions mainly through Trk receptors, and the neurotrophic signaling network is critical to the survival of neurons. However, therapeutic use of neurotrophins in treating neurodegenerative diseases is hampered by a number of pharmacological challenges, and the most significant challenge is their delivery into the central nervous system. Here, we reported that echinacoside, a small natural compound, elicits neuroprotection by activating Trk receptors and their downstream signal pathways. Echinacoside is the major active component of Cistanches Herba, a widely used Chinese herb with neuroprotective effects. We showed in this study that transient exposure to echinacoside is sufficient to protect neuronal cells and non-neuronal cells over-expressed with TrkA or TrkB against rotenone injury. Additional investigations on the mechanisms underlying suggested that transient treatment with echinacoside inhibits cytochrome c release and caspase-3 activation caused by ensuing rotenone exposure via activating Trk-extracellular signal-regulated kinase (ERK) pathway in neuronal cells. As echinacoside is able to cross the blood–brain barrier freely, it may have a promising potential in neurodegenerative diseases treatment.