ABSTRACT The anti‐inflammatory and neuroprotective potential of probiotic Lactobacillus strains has gained significant attention due to their ability to modulate oxidative stress and inflammation. In this study, two indigenous Lactiplantibacillus plantarum , LpJ5 and LpJ8, were evaluated for their anti‐inflammatory and neuroprotective properties to mitigate oxidative stress and enhance cell viability in neuroinflammatory models. Results indicate that LpJ5 significantly upregulated glutathione peroxidase (gpx) and glutathione (gsh) expression at 0.9 mM hydrogen peroxide (H 2 O 2 ). The probiotic strains also demonstrated significant anti‐inflammatory effects in lipopolysaccharide (LPS)‐induced BV2 and SH‐SY5Y cell models. Pretreatment with LpJ5 resulted in a 59.7% reduction in nitric oxide (NO) production in BV2 cells and a 56.7% reduction in SH‐SY5Y cells. LpJ8 showed comparable reductions of 49.2% and 47.3%, respectively. Additionally, LpJ5 pretreatment led to an increase in cell viability in BV2 and SH‐SY5Y cells. Both strains also reduced the expression of inflammatory markers such as iNOS, COX‐2, TNF‐α, IL‐1β, and upregulated BCL‐2 and IL‐10, with LpJ5 exhibiting stronger effects, particularly in the pretreatment phase. These findings demonstrate the antioxidant and anti‐inflammatory capabilities of LpJ5 and LpJ8 and thereby highlight potential mechanistic links and lay the groundwork for subsequent translational and clinical investigations. Thus making them promising candidates for therapeutic applications.