BACKGROUND: Multiple sclerosis (MS) is a persistent autoimmune condition characterized by inflammation and neurodegeneration. The current efficacy of treatments is limited, which has generated interest in developing neuroprotective strategies. Solid lipid nanoparticles (SLNs) and probiotics are potential drug delivery vehicles for targeting the CNS (Central nervous system), regulating immune responses, and supporting neuroprotection in neurological conditions. METHODS: The study investigates how SLNs containing RSG (rosiglitazone) and probiotics can protect the nervous system in cases of MS. We administered toxin EtBr (Ethidium bromide) from day 1 to day 7, later followed by the treatment from day 8 to day 35. During this time interval, various behavioural parameters have been performed. Further, after 35th day, blood plasma of animals was collected to study complete CBC profiling and animals were sacrificed. Then, biochemical and molecular studies, gross morphology of brain sectioning, histopathological evaluation and estimation of fatty acid content in fecal matter were performed. RESULTS: RSG shows neuroprotective effects by blocking the STAT-3 and mTOR signaling pathways and increasing the production of PPAR-gamma. GW9662, a PPAR-gamma antagonist given at a dose of 2 mg/kg (i.p), was utilized to evaluate the role of PPAR-gamma and to compare the efficacy of RSG and probiotic-loaded SLNs in potentially providing neuroprotection. The relationship between RSG and the STAT-3, mTOR, and PPAR-gamma pathways in MS was confirmed and validated using analysis. RSG and probiotic-loaded SLNs modulate the complete blood profiling of rats and improve the symptoms of MS. We assessed the diagnostic capabilities of different biological samples such as cerebrospinal fluid, blood plasma, and brain homogenates (specifically from the hippocampus, striatum, cortex, and midbrain) to analyze neurochemical changes linked to neurobehavioral changes in the progression of MS. CONCLUSION: The study showed that combining RSG and probiotics in an experimental medication form improved symptoms of MS more effectively than using RSG alone. This improvement is likely due to changes in STAT-3, mTOR, and PPAR-gamma signaling pathways.