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The search for experimental models mimicking an early stage of Parkinson's disease (PD) before motor manifestations is fundamental in order to explore early signs and get a better prognosis. Interestingly, our previous studies have indicated that 6-hydroxydopamine (6-OHDA) is a suitable model to induce an early degeneration of the nigrostriatal system without any gross motor impairment. Considering our previous findings, we aim to implement a novel system to monitor rats after intrastriatal injection of 6-OHDA to detect and analyze physiological changes underlying prodromal PD. Twenty male Sprague-Dawley rats were unilaterally injected with 6-OHDA (n = 10) or saline solution (n = 10) into the right striatum and placed in enriched environment cages where the activity was monitored. After 2 weeks, the amphetamine test was performed before the sacrifice. Immunohistochemistry was developed for the morphological evaluation and western blot analysis to assess molecular changes. Home-cage monitoring revealed behavioral changes in response to 6-OHDA administration including significant hyperactivity and hypoactivity during the light and dark phase, respectively, turning out in a change of the circadian timing. A preclinical stage of PD was functionally confirmed with the amphetamine test. Moreover, the loss of tyrosine hydroxylase expression was significantly correlated with the motor results, and 6-OHDA induced early proapoptotic events. Our findings provide evidence for a novel prodromal 6-OHDA model following a customized monitoring system that could give insights to detect non-motor deficits and molecular targets to test neuroprotective/neurorestorative agents. This study has been financially supported by the University of the Basque Country (UPV/EHU) PPG 17/51 and GIU 092/19, the Basque Government (Saiotek SA-2010/00028, ELEKIN, Engineering and Society and Bioengineering, and ELKARTEK 18/99), "Ministerio de Ciencia e Innovacion" (SAF2016 77758 R), FEDER funds, the European Union COST Action (CA15225, CA18106), DomusVi Foundation (FP18/76), and Government of Gipuzkoa (HELENA: Multisensory stimulation tools for Alzheimer Disease). CR appreciates the previous economic support received from UPV/EHU and the current postdoctoral fellowship received from Alfonso Martin Escudero Foundation.