A fluoroquinolone antibiotic called ciprofloxacin (CPX) is used to treat various bacterial diseases such as respiratory, urinary tract, gastrointestinal, and abdominal infections. This study is aimed to investigate the potential processes by which CPX may promote depression when given at three different doses. At rats, CPX was given orally in dosages of 12.5, 25 and 50 mg/kg per day for 14 days. The forced swimming test was used to assess this depression. Also, we studied the effects of CPX treatment on brain contents of serotonin (5-HT), g-amino-butyric acid (GABA) and excitatory amino acid transporter 2 (EAAT 2). Nitric oxide (NO) and malondialdehyde (MDA) measurements in the brain tissues were used to assess the role that oxidative stress played in the CPX-induced alterations. This study showed that depression-like behavior was only observed in the 50 mg/kg-treated group of CPX at the same time as 5-HT, GABA and EAAT2 levels decreased in the brain. Additionally, increased NO and MDA activity were found in the brain homogenates of the groups that received CPX compared to their controls, which showed increased oxidative stress and a compromised antioxidant defense mechanisms. In conclusion, the 50 mg/Kg CPX dose was more effective than the other two doses at inducing depression because it had a longer effect on swimming time, decreased brain 5-HT, GABA and EAAT 2 levels, and elevated oxidative stress markers; those were considered possible underlying mechanisms of depression caused by CPX.