Liver fibrosis is regarded as one of the most severe manifestations of liver diseases, which is marked with excessive cell proliferation and abnormal extracellular matrix deposition, leading to significant pathological distortions in liver tissue architecture and function. The current study aimed to assess the antioxidant and hepatoprotective effectiveness of Vitamin D (VD3) and Telmisartan (TEL) against liver fibrosis induced by thioacetamide (TAA) (200 mg/kg, i.p) in an in vivo rat model. Four groups were randomly divided, each with ten rats (n = 10): 1) healthy, 2) TAA-induced for 8 weeks, 3) prophylactic group, and 4) TAA-induced for 8 weeks, followed by VD3+TEL therapy for 8 weeks. Tissue samples were evaluated using histological techniques (H&E, Masson's trichrome stain), biochemical procedures, and gene expression analysis for Mmp9, TNF-α, p21, Col1α1, TIMP-1, Acta2, and IL-6. TAA led to liver damage and increased blood levels of ALT, AST, ALP, MDA, TNF-α, IL-6, and IL-1β in the fibrotic group. Fortunately, combined treatment of VD3 with TEL significantly reduced the severity of TAA-induced biochemical, molecular, and histopathological changes. Significant improvement in the histological morphology and structure of the liver parenchyma. VD3 with TEL reduced oxidative stress and inflammation and inhibited the TIMP-1/p21 signaling pathway and consequent cell senescence.