Being used in large quantities for some decades, antibiotics have been of little notice since their existence in the environment. Present study aims at investigating the optimization of Ciprofloxacin removal (CIP) in Thermally Activated Persulfate (TAP)/Aeration systems by Central Composite Design (CCD). The effect of operating parameters including initial pH, CIP concentration, Persulfate concentration and temperature on the removal process was investigated in order to find out the optimum conditions. Typically, high temperature, high Persulfate dose, and low initial CIP concentration increased the removal efficiency of CIP. At the tested pH range of 3-11, the highest removal occurred at pH 3.93. Finally, the effects of Mn3O4 Nanoparticles, N2 gas, and COD reduction in optimal condition were studied. Mn3O4 Nanoparticles and N2 gas in optimized conditions increased the removal efficiency from 93.41 to 90.1, respectively. The results showed that Thermally Activated Persulfate oxidation was the efficient process for the treatment of aqueous solution containing Ciprofloxacin due to the production of Sulfate radicals.