Alzheimer’s disease (AD) involves a progressive loss of neuronal integrity in which chronic neuroinflammation is increasingly recognized as a contributing factor. Sustained activation of innate immune pathways, including Toll-like receptor 4 (TLR4) signaling, has been linked to microglial reactivity and hippocampal dysfunction in experimental models of the disease. Lithium has been reported to exert neuroprotective and anti-inflammatory effects, yet the molecular pathways underlying these actions in AD remain poorly defined. Here, we investigated how long-term lithium exposure influences hippocampal protein networks in a triple transgenic mouse model of AD (3xTg-AD). Hippocampal tissue from wild-type and 3xTg-AD mice treated chronically with subtherapeutic (1 mM) or therapeutic (2 mM) lithium concentrations for eight months was analyzed using liquid chromatography–tandem mass spectrometry. Proteomic profiling revealed widespread lithium-associated changes in proteins related to immune response, cellular stress, and inflammatory regulation. Network-based analyses highlighted components of the TLR4/NF-κB and MAPK signaling pathways as prominent nodes that were reduced in lithium-treated animals relative to controls. Together, these data indicate that chronic lithium treatment is associated with a remodeling of hippocampal inflammatory signaling in a mouse model of AD. Although additional functional studies will be necessary to establish mechanistic links, the present findings support the view that lithium-sensitive immune pathways may be relevant to the modulation of neuroinflammatory processes in Alzheimer’s disease.