The extensive use of antibiotics has become a serious concern due to certain deficiencies in wastewater facilities, their resistance to removal, and their toxic effects on the natural environment. Therefore, substantial attention has been given to the detection of antibiotics because of their potential detriment to the ecosystem and human health. In the present study, a novel design of indium tin oxide (ITO) coated U-shaped fiber optic lossy mode resonance (LMR) biosensor is presented for the sensitive detection of the antibiotic ciprofloxacin (CIP). The performance of the designed U-shaped LMR sensor is characterized in terms of its sensitivity, full width at half maximum (FWHM), the figure of merit (FOM), and the limit of detection (LOD). For the proposed U-shaped LMR sensing probe, the various crucial factors such as the thickness (d) of the ITO layer, sensing region length (L), and bending radius (R) are optimized. The thickness of the ITO layer is optimized in such a way that two LMR curves are observed in the transmission spectrum and, thereafter, the performance parameters are evaluated for each LMR. It is observed that the designed U-shaped LMR sensor with optimized parameters shows an approximately seven-fold enhancement in sensitivity compared to the straight-core fiber optic LMR sensor. The numerical results revealed that the designed U-shaped fiber optic LMR biosensor can provide a maximum sensitivity of 17,209.9 nm/RIU with the highest FOM of 91.42 RIU-1, and LOD of 6.3 × 10-5 RIU for the detection of CIP hydrochloride in the concentration range of 0.001 to 0.029 mol∙dm-3. Thus, it is believed that the designed LMR biosensor can practically explore its potential use in environmental monitoring and biomedical applications and hence, opens a new window of opportunity for the researchers working in the field of U-shaped fiber optic LMR biosensing.