Fluoroquinolones are more likely than any other antibacterial drug classes to cause serious side effects. The purpose of this study is to assess the protective effects of vitamin E, curcumin, and ginger in male rats against the side effects of levofloxacin (LFX).Ninety male Wistar rats were placed into six groups, each of 15 animals. Groups 1 and 2 received distilled water or olive oil and kept as normal controls, while groups 3-6 received LFX [10 mg/kg body weight (BW)] alone or in combination with vitamin E (100 mg/kg BW.), curcumin (200 mg/kg BW.) or ginger (200 mg/kg BW.), respectively.  All medications were administered orally via gavage once a day for 5 successive days. Samples of blood were collected at zero day , 7^th and 14^th day post-treatments for biochemical analysis, while liver and kidney tissues were dissected and subjected to antioxidants estimation. Levofloxacin administration caused hepatic and renal damage evidenced by significant increase in serum liver enzymes, urea (76.43±3.70, 72.67±0.47, 75.00±6.42), creatinine (2.48±0.01, 2.48±0.01, 2.50±0.01), total cholesterol (166.67±6.81, 174.00±4.04, 176.00±2.88), triglycerides (269.67±5.84, 289.33± 4.91, 249.67±1.86), and low density lipoprotein- cholesterol (LDL- C) (243.00±7.09, 213.67± 5.03, 226.33±5.45) levels. Meanwhile, significant decline in serum levels of high density lipoprotein- cholesterol (HDL- C) (20.00±1.11, 23.33±3.38, 20.10±1.53), total protein (5.77±0.03, 5.97±0.09, 5.87±0.09), albumin (3.45±0.03, 3.60±0.06, 3.57±0.09)and A/G ratio (1.49±0.02, 1.51±0.05, 1.55±0.09) were determined in relation to normal control at zero, 7^th and 14^th day post-treatments, respectively in a time dependent manner. The superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities in the liver (1.50±0.13, 1.67±0.18, 1.60±0.15; 2.02±0.38, 2.81±0.25, 3.30±0.37) and kidney (24.97±1.04, 21.33±1.33, 26.33±1.71; 3.15±0.14, 2.13±0.36, 2.44±0.28)tissues were significantly decreased in all levofloxacin- exposed rats compared to control values in the liver (3.00±0.11, 3.33±3.13, 3.33±0.16 for SOD; 19.76±0.03, 19.18±0.05,  18.42±0.13 for GPx) and kidney (71.33 ± 2.60, 67.67±0.88, 66.00±1.73 for SOD; 8.32±0.08, 8.30±0.04, 7.81±0.06 for GPx).  However, the hepatic and renal malondialdehyde (MDA) concentrations (74.51±0.69, 80.97±0.41, 95.88±0.52; 66.58±0.14, 65.09±0.12, 65.23±0.14) were significantly increased compared to the control (11.82±0.01, 11.82±0.001, 11.11±0.03; 30.88±0.03, 33.20±0.03, 32.83±0.04). Co-administration of LFX with vitamin E, curcumin or ginger attenuated the elevated liver enzymes, renal damage biomarkers, lipogram and hepato-renal MDA, with elevation of tissues antioxidants. From this study, biochemical results indicated that levofloxacin induced hepato-renal alterations in rats over time, and that curcumin or ginger medications may be more effective when used prophylactically rather than curatively.