Nonalcoholic steatohepatitis (NASH) is an inflammation of the liver and a menace to human health. To treat NASH various pharmaceutical products have been used, but their prohibitive side effects limit their effectiveness. NASH, a multihit hypothesis involves high-fat diet and signals from the gut to the liver. Lactobacillus plantarum (probiotic) and aged garlic extract (AGE, a prebiotic) are antioxidative and anti-inflammatory and may be a latent combination therapy for NASH. The NASH model was developed using Wistar rats and treatments were administered to understand the mechanism. Initially, in the in vitro models, transepithelial electrical resistance (TEER) 2'-7'-dichlorodihydrofluorescein diacetate (DCFDA), 4-6-diamidino-2-phenylindole (DAPI) labeling and Oil Red O (ORO) conducted on HepG2 and Caco2 cells. Afterwards, in in vivo studies rat liver tissues were examined through confocal microscopy using the ORO staining and hematoxylin and eosin (H/E) stain, malondialdehyde (MDA), and biochemical indices were recorded. The levels of patatin-like phospholipase domain-containing protein 3 (PNPLA3) and sterol regulatory element binding protein-1c (SREBP-1c), peroxisome proliferators activated receptors (PPARs)-α, inflammatory, and apoptotic biomarkers were quantified by qRT-PCR. Synbiotic reduced the hepatic inflammation and apoptosis examined through the levels of PNPLA3, SREBP-1c, IL-6, TGF-β, Bcl-2, and caspase-3 in NASH models. In turn, the gram-negative species and bacterial translocation associated were reduced. Consequently, the Insilco analysis supports the theory that each (eight) bioactive compound of AGE targets PNPLA3 and enhances the PPAR-α activity. Additionally, PPAR-α inhibitors upregulated the PNPLA3 and SREBP-1C expression. As a result, the synbiotic may inhibit NASH progression by affecting PNPLA3/SREBP1-c through PPAR-α.