Sustained systemic inflammation causes neuroinflammation and increases seizure risk, yet mechanisms linking inflammation and epileptogenicity remain poorly understood. Vagus nerve stimulation (VNS) suppresses systemic cytokines and modulates microglial activity after acute inflammatory challenges, but it is unknown whether these effects persist with sustained inflammation. Here we employed daily VNS in a rat model of endotoxemia induced by five daily lipopolysaccharide (LPS) injections. Rats received VNS from an implanted, wirelessly powered neurostimulator. Seizure susceptibility was assessed with pentylenetetrazol infusion, and peripheral and central inflammation were evaluated with serum cytokines, microglial cytology, and transcriptomics. Our findings show that sustained LPS exposure lowers seizure thresholds and induces strong systemic and central inflammatory responses. Our VNS regimen suppressed epileptogenicity, elevated serum IL-10, and shifted splenocyte gene signatures toward quiescence but had only subtle, region- and sex-specific effects on microglia and central inflammatory markers. These results suggest that VNS can suppress sustained systemic inflammation and mitigate inflammation-associated epileptogenicity, although its anti-epileptic effects may also involve non-neuroinflammatory mechanisms. A caveat is that sustained LPS exposure may also engage endogenous anti-inflammatory pathways and blunt the anti-inflammatory effects of VNS. This work highlights the potential of VNS to prevent inflammation-induced hyperexcitability via complex, sex-dependent neuroimmune and other effects.