The purpose of the present study was to evaluate the possible ameliorative role of Thymus vulgaris (T. vulgaris) essential oil against Escherichia coli O157:H7 (E. coli O157:H7) deleterious effects in both blood and different tissues of rats by assessing the hematological, biochemical and immune-inflammatory parameters besides the histopathological alterations in the different organs. Forty male rats were randomly divided into four equal groups as follows: group I served as control, group II orally inoculated with E. coli O157:H7 at a dose of 1.0 × 109 cfu/ml, group III orally received 250 mg/kg BW T. vulgaris oil daily for 7 days and group IV orally inoculated with E. coli O157:H7 as the same dose of group II and orally received T. vulgaris oil as the same dose and duration of group III. Bacterial challenge in groups II and IV was once at the beginning of experiment and administration of oil began after 72 h from bacterial inoculation. At the end of the study, blood was sampled and complete blood picture, liver and kidney function alongside immunoglobulins and cytokines concentrations were estimated and tissues of large intestine (colon), liver and kidneys were collected for histopathological examinations. The results revealed that there was an increase of red blood cells count, hematocrit value and hemoglobin concentration besides white blood cells and thrombocytes counts and substantial increment of serum markers of hepatorenal damage such as the activities of transaminases and concentrations of bilirubin (total, direct and indirect), total proteins, albumin, creatinine and urea in E. coli O157:H7-challenged group. Also, there was a considerable increase in serum immunoglobulins M and G, interleukin 6 and 8 and tumor necrosis factor alpha as well as decreased serum alkaline phosphatase activity. Moreover, T. vulgaris oil could partially improve the hematological, biochemical and histopathological alterations induced by E. coli O157:H7 without any significant alterations in all measured parameters when used alone. The study concluded that the T. vulgaris oil relatively diminished the alterations in hematological parameters, hepatic and renal function markers and immune-inflammatory variables alongside the histopathological changes in different organs induced by E. coli O157:H7. The ameliorative effects of T. vulgaris oil are mediated through its anti-inflammatory, antioxidant and immunomodulatory activities.