Background/Objectives: Systemic inflammation is a known driver of neurodegenerative processes, with amyloid accumulation and neuronal loss. The Interleukin-33 (IL-33)/Suppression of Tumorigenicity 2 (ST2) signaling pathway has emerged as a critical immune regulator with dual roles in maintaining brain health. However, its role in pathological alterations in the central nervous system, and more specifically in the hippocampus during endotoxemia, is not fully elucidated. The aim of this research was to determine the role of the IL-33/ST2 axis in neurodegenerative processes in mice caused by systemic inflammation. Methods: BALB/c wild-type (WT) and ST2-deficient (ST2^−/−) mice were challenged with systemic lipopolysaccharide (LPS) for 7 days. One subgroup of WT mice also received exogenous IL-33. Expression of Iba1, myelin, and amyloid was detected by immunohistochemistry, the TUNEL assay was used for detection of apoptosis, flow cytometry was used to assess microglial phenotype, and RT PCR was used to detect the expression of cytokines. Results: LPS administration induced demyelination and amyloid deposition in the hippocampus. These pathological changes were the most pronounced in ST2^−/− mice, which exhibited an aggressive microglial phenotype, excessive production of IL-1β and massive apoptosis in the hippocampus. Conversely, exogenous IL-33 treatment in WT mice exerted a profound neuroprotective effect. IL-33 induced phagocytic morphology of Iba1-positive cells, redirected microglia toward a restorative M2 phenotype, and significantly upregulated IL-10. This immunomodulation led to the preservation of myelin integrity, a reduction in amyloid load, and the near-complete prevention of hippocampal apoptosis in IL-33 treated mice. Conclusions: This study identifies the IL-33/ST2 axis as an important defense signaling pathway in neuroinflammation induced by systemic LPS administration. By promoting a regulatory microglial state and balancing the IL-10/IL-1β ratio, IL-33 prevents neuroinflammation and neurodegeneration. Our data highlight the pharmacological potential of the IL-33/ST2 axis in counteracting amyloid-related pathologies.