Huntington's disease (HD) is an incorrigible neuropsychiatric disorder with reduced cognition and motor abnormalities. Piperine (PIP) is an alkaloid with antioxidant, anti-inflammatory, and neuroprotective activities; however, poor therapeutic efficacy limits its further use. The current study focuses on the enhanced therapeutic potential of PIP@CM against an experimental zebrafish model of HD. PIP@CM was fabricated using spray drying technology, followed by solid-state investigations. We performed in vitro release and in vitro antioxidant activity (DPPH assay) of PIP and PIP@CMs. In addition, in vivo studies were conducted on zebrafish using 3-nitropropionic acid (3-NPA) (60 mg/kg) as a neurotoxin and treated with PIP (5 mg/kg) and PIP@CM (25 mg/kg equivalent to 5 mg/kg PIP). After dosing, various in vivo studies (behavioral, biochemical, and histological) were conducted. The solid-state characterization techniques revealed the loss of crystallinity after micelles formation. In vitro release and antioxidant assays showed higher release and enhanced activity of PIP@CM. In vivo studies revealed that 3-NPA administration causes HD, as evidenced by the results of open field test (OFT) and novel tank diving test (NTD) tests. Moreover, 3-NPA causes an increase in oxidative stress, as confirmed by biochemical and histopathological studies. PIP@CM treatment significantly improved behavioral performance in OFT and NTD tests and reduced oxidative stress markers as compared to pure PIP and untreated HD model.