In this research, we synthesized BiOI/NH2-MIL125(Ti) via solvo-thermal method to investigation of oxytetracycline (OTC) degradation in photocatalytic-ozonation process. The results of the XRD, FESEM, EDAX, FTIR, UV–Vis, TEM, XPS, and BET analyzes indicated that the catalyst BiOI/MOF was synthesized with excellent quality. Design of experiment (DOE), ANOVA statistical analysis, interaction of parameters and predicated optimum condition was done based on CCD. The effect of catalyst dose (0.25–0.5 mg/l), pH (4–8), reaction time (30–60 min) and O3concentration (20–40 mN) at 10 mg/l of OTC on PCO/O3process was optimized. Based on P-value and F-value coefficients (0.0001, 450.3 respectively) the model of OTC (F-value = 2451.04) and (P-value = 0.0001) coefficients, the model of COD removal was quadratic model. Under optimum condition pH 8.0, CD = 0.34 mg/l, RT = 56 min and O3concentration = 28.7 mN, 96.2 and 77.2% of OTC and COD removed, respectively. The reduction of TOC was 64.2% in optimal conditions, which is less than the reduction of COD and OTC. The kinetics of reaction followed pseudo-first-order kinetic (R2= 0.99). Synergistic effect coefficient was 1.31 that indicated ozonation, presence of catalyst and photolysis had a synergistic effect on OTC removal. The stability and reusability of the catalyst in six consecutive operating steps was acceptable and 7% efficiency decreased only. Cations (Mg2+, and Ca2+), SO42−had no influence on performing the process, but other anions, organic scavengers, and nitrogen gas, had an inhibitory effect. Finally, the OTC degradation probably pathway includes direct and indirect oxidation that decarboxylation, hydroxylation, demethylation and were the main mechanism in OTC degradation.