The confined liquid impinging jets (CLIJ) technique was applied as a simple and effective approach to reducing the particle size of loratadine to enhance its solubility. The effect of anti-solvent (AS) to solution (S) flow rate ratio, organic phase concentration, Reynolds number (Re), and stabilizer concentration was investigated in this reduction process. After the synthesis, the chemical and physical properties of loratadine nanoparticles were determined through different characterization and analytical techniques. The results indicated that the particle size of loratadine decreases from 320 nm to 80 nm by increasing the AS/S ratio from 1 to 25. It was found that the particle size of loratadine was unchanged at the higher AS/S ratios. The loratadine nanoparticle size was optimized by changing the solution concentration, Re, and Tween 80 as a stabilizer. The finest loratadine nanoparticle size of about 53 nm was obtained with a narrow size distribution, which corresponds to solution concentration of 35 mg/mL, Re of 5687, and 0.1% (w/v) stabilizer concentration. It was revealed that the optimized loratadine nanoparticles completely dissolved after 11 min, indicating the loratadine nanoparticle dissolution rate 50 times faster than raw loratadine.