Active pharmaceutical ingredients (APIs) can be assured to be safe and effective with the help of stability-indicating procedures. An accurate comparison comprising the utilization of capillary zone electrophoresis (CZE) and ultra-performance liquid chromatography (UPLC) for the sensitive and accurate measurement of ciprofloxacin (CPF) in the presence of its major photo-degradation product was conducted. The CZE and UPLC working conditions were optimized to obtain the best pattern of separation for CPF and its photo-degradant. The linearity range of the cited techniques was confirmed to be 0.5 to 50 µg/mL. A thorough validation scheme according to the ICH-Q2B criteria was performed, including linearity, accuracy, precision, robustness, detection, and quantification limits. Selective quantification of CPF in the presence of up to 90% of its main photo-degradant was carried out using the proposed methods. For the analysis of CPF in tablet and intravenous (I.V.) solution forms, the CZE and UPLC procedures were applied. The suggested methods can be applied to keep an eye on the safety and efficacy of CPF in either bulk or dosage forms.