Parkinson's disease (PD) is a complex pathology presenting with motor symptoms coupled with a variety of non-motor symptoms originating in the central nervous system or the periphery, resulting in a complex multisystem disease. The development of therapeutic approaches to slow or stop disease progression remains the greatest unmet therapeutic need for PD. The immune system plays a pivotal role in the central and peripheral pathology of PD, reacting to misfolded α‐synuclein with neuroinflammation and dysregulation of peripheral immune responses. Here, we tested the neuroprotective properties of the immunomodulatory imide drug (IMiD) pomalidomide (Pom) in a translational rat model of PD based on the intranigral bilateral infusion of toxic oligomers of human α-synuclein (H-αSynOs), which shows both motor and cognitive impairments. Pom was chronically administered starting one-month post-infusion of H-αSynOs (20 mg/kg; i.p. three times/week for two months). The intranigral infusion of H-αSynOs induced impairments in motor performance and cognitive deficits, that were attenuated by Pom. Moreover, H-αSynOs-infused rats displayed a 45% cell loss within the substantia nigra (SN) that was largely abolished by Pom. H-αSynOs infusion induced a neuroinflammatory response in the substantia nigra and in cognition-related brain regions, as well as a systemic inflammatory response as measured by blood cytokines levels, that were both reduced by Pom treatment. We provide evidence of the disease modifying potential of Pom, and a rationale for clinical testing of this drug in PD patients.