Despite the exploration of pharmaceutical and natural liver-protecting drugs, the number of hepatotoxicity deaths continues to rise. Milk thistle flavonoids, silymarin, have been widely investigated and demonstrated liver disease protection. Poor solubility and absorption restrict silymarin bioavailability. Effervescent formulations may boost silymarin absorption by improving gastrointestinal solubility. Our study compared the effectiveness of silymarin effervescent formulation in protecting the liver from thioacetamide (TAA)-induced oxidative damage at both low and high doses. Study findings may have an implication on chemotherapy-induced off-target harmful oxidative insult. 24 adult male rats were separated into normal control, hepatotoxic (TAA) (100 mg/kg body weight), and TAA plus silymarin (50 and 100 mg/kg b.wt) groups. Serum liver enzyme, hepatic antioxidant, lipid peroxidation, and inflammatory indicators were measured. The modest dose's great bioavailability was shown by its potency being identical to the doubled dose. TAA caused hepatic injury, as evidenced by elevated liver enzymes (ALT and AST) and tissue levels of MDA, TLR4, TGFβ1, TNF-α, IL-6, NF-κB, and p-NFκB. TAA also decreased tissue SOD, GSH, and HO-1 levels as well as Nrf2 level and expression. Increased gene expressions of Akt, PI3K, and TLR4 were observed. Silymarin's antioxidant and anti-inflammatory actions reduced hepatotoxicity via upregulating Nrf2/HO-1 and downregulating PI3K/Akt and TLR4/NFκB pathways. This study shows that effervescent silymarin formulation is a powerful bioavailable treatment for liver oxidative toxicity in chemotherapy-related toxicities.