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Cancer is the most threatening disease worldwide. Noticeably, most cancer patients are immune-compromised, so they are more susceptible to infections. The combination of the tyrosine kinase inhibitor nilotinib (NIL) with broad-spectrum antibiotics such as the fluoroquinolone ofloxacin (OFL) is clinically rationalized based on NIL's immunosuppressive effects and the need for infection prophylaxis in cancer patients. However, there is no published method for their in-vivo simultaneous determination in clinical biological specimens to support their pharmacokinetics and therapeutic monitoring. This study focuses on the development of a miniaturized capillary electrophoresis system-assisted with photodiode array detection (CE-PDA) for the simultaneous determination of NIL and OFL in clinical settings for analysis of plasma samples containing NIL and OFL. The conditions of electrophoretic separation of NIL, OFL, and sarafloxacin (SAR, as an internal standard), and the analytical procedures were successfully established. The electrophoretic separation of NIL, OFL, and SAR, as the internal standard, was achieved utilizing a fused silica capillary (58 cm length × 75 μm internal diameter) maintained at 25 °C using a background electrolyte solution composed of borate buffer (20 mM, pH 9.3) at a separation voltage of 30 kV. The linear range of the CE-PDA method in spiked rat plasma was determined to be 0.5-80 µg mL^- 1 for NIL and OFL. The CE-PDA approach exhibited maximum sensitivity, with lower limits of quantitation (LLOQ) of 0.3 µg mL^- 1 for NIL and 0.4 µg mL^- 1 for OFL. These LLOQs were experimentally validated according to US-FDA guidlines and were lower than the calibration range's starting point to ensure reliable quantification. In addition, the CE-PDA system was validated and subsequently applied to real plasma samples withdrawn from rats received concurrent administration of NIL and OFL. The plasma protein was precipitated by acetonitrile. The validation parameters were determined and found to comply with the requirements for the Food and Drug Administration (FDA) guidelines for validation of bioanalytical procedures. The sustainable features of the system and its environmental impact were confirmed using seven different metric tools. Finally, the proposed CE-PDA is time-saving and cost-effective, enabling its beneficial applications in the therapeutic drug monitoring of NIL and OFL in oncology clinics.