Background: There is a constant hunt for the development of new therapeutic alternative to address Alzheimer's disease (AD) due to its failing attempts in the evolution of new therapies and suboptimal results from the existing pharmacological interventions for the treatment of this severe neurodegenerative disease. Vernonia anthelmintica is an extensively used medicinal plant in Indian traditional medicine with wide range of therapeutic values. However, there is insufficient scientific documentation available for its protective effect against cognitive disorders. Objectives: The objective of the current investigation is to explore the neuroprotective activity of methanolic extract of V. anthelmintica (MEVA) in amyloid-beta (Aβ) (1–42) infused sporadic model of AD. Materials and Methods: Adult healthy male Wistar rats were treated orally with 250 mg/kg and 500 mg/kg of MEVA for 28 days, after a week from intracerebroventricular (i.c.v) infusion of Aβ (1–42) peptides followed by assessment of neurobehavioral deficits. Subsequently, animals were euthanized and brains were collected for estimation and quantification of neurochemical biomarkers including antioxidant enzymes, neurotransmitters, plaque load, and inflammatory mediators. Results: Dose-dependent reversal of cognitive impairment was observed upon MEVA treatment in amyloid intoxicated rats as corroborated by improved learning and memory and diminished oxidative stress, cholinergic hypofunction, and neuroinflammation induced by Aβ (1–42). Conclusion: Collectively, evidence-based data suggested the promising neurotherapeutic potential of V. anthelmintica and thereby can stand as a novel entity for curbing AD pathology.