Obesity is considered a health issue associated with increased morbidity and a risk factor for multiple conditions, such as type 2 diabetes, cardiovascular diseases and infections. It may affect the pharmacokinetics and pharmacodynamics of many drugs, including antimicrobials like ciprofloxacin. Regrettably, data on ciprofloxacin's efficacy in obese patients remain scarce. This study aims to evaluate the impact of obesity on the efficacy of ciprofloxacin in treating Gram-negative bacterial infections. A retrospective multicenter cohort study was conducted in two tertiary hospitals in Saudi Arabia. Adult patients (≥18 years) treated with ciprofloxacin for confirmed Gram-negative infection between January 2017 and April 2023 were included. Patients were excluded if they received ciprofloxacin empirically, had inadequate source control within 72 h, or had missing weight and height information at ciprofloxacin initiation. The primary outcome was clinical cure, defined as the resolution of the clinical infection manifestations without additional therapeutic management by the end of treatment. Other secondary and safety outcomes were also assessed. A total of 99 patients were included, divided into obese (n = 42) and non-obese (n = 57) groups. The obese group had a significantly lower median age (50 years) compared to the non-obese group (64 years) (p = 0.002). The obese group had fewer male patients (38.10% vs. 68.42%; p = 0.004), higher body weight (90 (81-97) vs. 63 (55-70) days; p < 0.001), and lower height (158 (155-165) vs. 165 (158-172) days; p = 0.008) compared to non-obese. Urinary tract infection was the most common type, with Escherichia coli being the most common isolate. The median hospital length of stay was shorter in the obese group than in the non-obese group (1 vs. 3 days, p = 0.007). There were no significant differences in clinical cure rates between obese (85.71%) and non-obese (85.96%) patients (p = 1). No significant differences were observed in terms of in-hospital mortality, 30-day mortality, or 60-day infection recurrence rates between the two groups. Microbiological eradication was not achieved in the obese group, whereas a 10.53% eradication rate was observed in the non-obese group (p = 0.037). However, the majority of the patients had indeterminate eradication. The incidence of adverse drug reactions (ADRs) was lower in the obese group (4.76%) compared to the non-obese group (17.54%, p = 0.066). Treatment with ciprofloxacin in obese patients has similar efficacy and safety outcomes compared to non-obese patients with infections due to Gram-negative pathogens.