Non-alcoholic steatohepatitis (NASH) may be associated with tissue fibrotic changes and can be treated via different therapeutic tools which may however either initiate weak or long-term side effects that minimize its use. Empagliflozin (EMPA) is an oral anti-diabetic drug which has characteristic effects during hepatic steatosis regarding lipid accumulation and insulin resistance. In this study, we aimed to investigate an additional mechanism through which EMPA can exert and potentiate its anti-inflammatory and anti-fibrotic effects in NASH rat model. Male Wistar albino rats fed on high fat diet (HFD) and 20% fructose in drinking water for 18 weeks and received EMPA (30 mg/kg/day, orally) starting from week 11. Body and liver weights, homeostatic model assessment of insulin resistance (HOMA-IR), lipid profile, liver function tests, other biochemical and histological parameters were determined. HFD joined with fructose intake significantly increased body and liver weights, HOMA-IR value, hepatic inflammatory and fibrotic markers, liver transaminases, hepatic expression of nuclear factor-kappa B (NF-κB), sex determining region Y box 9 (SOX 9), and osteopontin (OPN) with significant decrease in hepatic osteocalcin (OCN). Intense hepatic lesions with severe microsteatosis and deposition of collagen fibers were clearly observed. Effectively, EMPA restored the normal liver functions, downregulated hepatic inflammatory cytokines, NF-κB, SOX 9, OPN, and increased OCN level. These results highlight another pathway illustrated the anti-fibrotic effects of EMPA against liver fibrosis probably through downregulation of NF-κB/SOX 9/OPN signaling along with upregulation of hepatic OCN which may potentiate the valuable anti-inflammatory and anti-fibrotic effects of EMPA.