<p>Ciprofloxacin, a widely used oral fluoroquinolone antibiotic, requires precise control over crystallization to ensure optimal downstream processing and final product efficacy. The current study elucidates the application of ultrasound-assisted antisolvent crystallization to produce smaller crystals and enhance yield. Concurrent ultrasonic irradiation and antisolvent introduction via peristaltic pump were employed to modulate the precipitation process aiming to minimize the volume-weighted mean diameter (D[4,3]). Optimized ultrasound parameters established as 140 W ultrasonic power, 80% duty cycle, and 10-minute irradiation time, yielded a significant reduction in mean particle size ( D[4,3] = 2.27 ± 0.02 µm) and an increase in yield (80.21 ± 1.36%) at 1:9 solvent to antisolvent ratio, 100 mL/min antisolvent addition rate, 500 rpm stirring rate and 3 h standing time. In contrast, conventional crystallization conducted under identical conditions but without ultrasound produced larger crystals ( D [4,3] = 2.27 ± 0.02 µm) and lower yield (76.43 ± 1.15%). Even the best-case conventional crystallization at 1:9 solvent to antisolvent ratio, 100 mL/min antisolvent addition rate and 1000 rpm stirring rate resulted a yield of 79.04 ± 0.55% and a D[4,3] = 2.27 ± 0.02 µm. Characterization studies confirmed that ultrasound treatment preserved the chemical structure and crystal morphology of ciprofloxacin. With an ultrasonic energy consumption of approximately 0.019 kWh under the optimized conditions, the study demonstrates the economic feasibility and intensification benefits of ultrasound-assisted crystallization of ciprofloxacin.</p>