Abstract <p>General anesthetics in some patients may lead to neurotoxic complications, including apoptosis in neuronal cells and postoperative cognitive disorder. This study aims to systematically review and investigate the mechanistic effects of polyphenols in countering anesthetics-induced neurotoxicity in performing various surgical interventions. This systematic review was done according to the PRISMA 2020 guideline. Studies before November 2, 2024, were searched by selected keywords in Scopus, Web of Science, PubMed/MEDLINE, and the Cochrane Library to identify related studies. After screening, the most critical data and outcomes were extracted and reviewed. Included studies have shown that polyphenols have promising effects on neurons in protecting against anesthetics-induced neurotoxicity through antioxidant and anti-inflammatory activities through increasing endogenous antioxidant, heme oxygenase 1 (HO-1), reducing lipid peroxidation, nitric oxide, inhibiting proinflammatory cytokines, inhibited <i>c-Fos</i> expression, microglial activation, and M2-like polarization. They also improved mitochondrial structure and dynamics by increasing adenosine triphosphate (ATP) production, elevating mitochondrial membrane potential (ΔΨm), and modulating mitochondrial fission markers. Moreover, polyphenols reduced apoptosis by improving Bcl-2 and Bcl-xL, inhibiting Bax, BAD, caspase-3, and 9. They enhanced cell survival by increasing expressions of survivin, xIAP, c-IAP-1, and c-IAP-2 and activating the autophagy pathway via improving beclin-1, LC3-II/LC3-I ratio. Furthermore, polyphenols can improve memory, behavior, and cognitive function through sirtuin 1 (SIRT1), brain-derived neurotrophic factor (BDNF) activation, and attenuated inflammation. Additionally, polyphenols play a role in modulating neurotransmitters and calcium channels. Preclinical studies showed that polyphenols attenuated anesthetics-induced neurotoxicity and associated complications.</p>