Background: Linezolid (LNZ) is a broad-spectrum antibacterial agent that is usually used to treat bacterial infections. However, it is associated with adverse hepatic effects, including myelosuppression and hepatotoxicity. Aim: This study aimed to investigate the biochemical and histopathological changes in the liver induced by LNZ treatment and to evaluate the protective effect of vitamin E and Echinacea purpurea (immulant) combined with LNZ as a hepatotoxicity-inducing agent. Methods: Forty-nine male Sprague–Dawley rats were randomly divided into seven groups: a control (distilled water, 0.5 ml/200 g/day), Tween 80 (0.5 ml/200 g/day), LNZ (54 mg/kg b.wt), vitamin E (Vit E) (90 mg/kg b.wt), and immulant (15.75 mg/kg b.wt), while the sixth and seventh groups received a combination of Vit E (90 mg/kg b.wt) and LNZ (54 mg/kg b.wt), and E. purpurea (15.75 mg/kg b.wt) and LNZ (54 mg/kg b.wt), respectively. Results: After 14 days of treatment, the LNZ-treated group exhibited a noteworthy decrease in the hematological profile and crucial changes in the serum levels of liver enzymes, bilirubin, proteins, and lipid profiles. Furthermore, hepatocellular apoptotic cells, shrunken nuclei, hydropic degeneration, and apoptotic (caspase-3) expression in the liver were identified by histopathological immunohistochemical analysis. Vit E or E. purpurea treatment, along with LZN, abridged these opposing effects, indicating a protective effect of Vit E and E. purpurea. Conclusion: Vit E or E. purpurea provides a protective effect against LNZ-induced hepatic toxicity, suggesting that a simultaneous antioxidant remedy may protect the liver during LNZ treatment.