BACKGROUND: Osteopontin (OPN) has emerged as a pivotal molecule in Alzheimer's disease (AD), with studies indicating its potential to act as both a neuroprotective agent and a contributor to neurodegeneration. This systematic review aims to elucidate the roles of OPN in AD pathogenesis through inflammatory pathways. METHODS: We conducted a comprehensive analysis of current literature on OPN's involvement in AD, focusing on its signaling pathways, cellular interactions, and regulatory mechanisms. We searched PubMed, EMBASE, and Scopus databases by the keyword of Alzheimer's Disease and Osteopontin. Our date search was in 1990 until July 1, 2024 with no language limitation. RESULTS: In a review of 758 studies, a total of 15 reports met the eligibility criteria and were included. Among the findings, four studies provided evidence supporting the protective mechanism of OPN within the context of AD. Eleven studies explain the inflammatory role of OPN. OPN has been shown to play a role in synaptic pruning, microglial activation, and the inflammatory processes associated with AD. Additionally, OPN is implicated in facilitating cellular communication and serves as a chemotactic molecule. It is suggested that the protective effects of OPN are predominantly mediated by the c fragment of the protein and are most prominent in the early stages of AD progression. CONCLUSION: OPN in AD has dual effects-protecting neurons and contributing to their degeneration. Future research should enhance its protective mechanisms, target specific signaling pathways, and develop therapies to slow AD progression.