Parkinson ́s disease is a complex pathology marked neurodegeneration in dopaminergic neurons of the nigrostriatal system. The early prodromal phase has been recognized for the presence of non-motor symptoms that could be predictive of later motor disease. By inducing dopaminergic neuron death with 6-hydroxydopamine (6-OHDA) in male Wistar rats we have observed alterations in cognitive functions within 3 weeks of the surgery. We aimed to test the potential of TGF-β3, a trophic and anti-inflammatory factor, to mitigate these early changes. We administered an adenoviral vector containing the TGF-β3 gene (RAd-TGF-β3), or its control, 14 days after 6-OHDA (or vehicle) surgery. On day 21 we performed the Barnes Maze test, the Novel Object Recognition test and the Modified Y-Maze. We found that RAd-TGF-β3 in animals with 6-OHDA induced a better performance in these tests compared to animals administered with the control vector. At this time we demonstrated an anti-inflammatory effect measuring pro-inflammatory factors’ expression (IL-1, IL-6, TNF-α) in the hippocampus, as well as glial activation markers (CYP46, IGF-1), observing a reduction with RAd-TGF-β3 in comparison to 6-OHDA animals. Moreover, latency values in Barnes Maze correlate more with expression values of TNF-α than with other cytokines. We conclude that the overexpression of TGF-β3 can overcome the damaging processes induced by 6-OHDA and therefore has potential to treat parkinsonism’s early impairments.