<p><i>Aegiceras corniculatum</i> (AC), a mangrove species widely recognized for its diverse pharmacological properties, has attracted significant attention recently due to its antioxidant, anti-inflammatory, and antimicrobial activities. Despite this, the neuroprotective potential of AC, particularly in the context of neurodegenerative disorders such as Parkinson’s disease (PD), remains largely unexplored. Due to the growing interest in plant-derived compounds for the management of PD, investigating the therapeutic relevance of AC could provide new insights into alternative strategies for neuroprotection. The present study aimed to evaluate the neuroprotective ability of the leaf extract of AC against PD. Preliminary phytochemical analyses were conducted to identify the presence of bioactive compounds in the AC extract (ACE). The antioxidant capacity of ACE was evaluated using three standard assays: 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging assay, ferric reducing antioxidant power (FRAP) assay, and hydrogen peroxide (H₂O₂) scavenging assay. We used the MPTP-induced PD model established in an SH-SY5Y human neuroblastoma cell line as well as in the U87-MG glioblastoma cell line. MTT assay was conducted to measure the cell viability, and further, 2′,7′-dichlorofluorescin diacetate (DCFDA) assay was used to measure the reactive oxygen species (ROS). Glutathione peroxidase (GPx) enzyme activity was determined by a chromogenic reaction-based assay. Western blot analysis was used to assess the expression levels of SNCA protein. The ACE was found to contain a diverse range of phytochemicals, including polyphenols, flavonoids, and terpenoids. Among the ethanolic, hydroethanolic, and aqueous extracts evaluated, ethanolic ACE (eACE) exhibited the highest antioxidant activity. The SH-SY5Y cell line demonstrated significantly higher neuroprotective potential to eACE treatment compared to the U87-MG cell line. Moreover, eACE markedly attenuated intracellular ROS levels and enhanced glutathione peroxidase (GP_X) enzymatic activity. In line with these effects, eACE also significantly downregulated the expression of the SNCA gene, suggesting its potential modulatory role in oxidative stress-related neurodegeneration. AC exhibited notable neuroprotective effects in an in vitro model of PD. These effects are likely mediated through the attenuation of oxidative stress and neuroinflammation, inhibition of apoptosis, and preservation of cellular energy metabolism. The results suggest that the extract of AC may provide important insights for developing therapies that modify the progression of PD. Elucidating the underlying mechanisms could inform the creation of innovative treatments designed to slow or alter the trajectory of PD. The present study emphasizes the potential benefits of AC with contemporary scientific investigation to address the unmet needs of patients suffering from PD.</p> Graphical Abstract <p></p>