This report aims to develop and validate an HPLC method using the concepts of quality by design and design of experiments for the quantification of omeprazole. Design of experiments was performed in MODDE, and the studied parameters were temperature, percentage additive, ionic strength, and pH. It was concluded that ionic strength was not a significant factor interacting with the responses. The separations were performed on an isocratic system with a diode-array detector. The mobile phase consisted of acetonitrile and ammonia buffer pH 8.7 (30/70). The stationary phase was an XBridge C18 column with a flow rate of 1 mL∙min-1. The method was validated by examining the specificity, precision, linearity, sensitivity, and robustness. A calibration curve of 2 µg∙mL-1 to 200 µg∙mL-1 was constructed. It was linear in this range (R2 = 0.999) however with a bad intercept value (b = 17.489). The sensitivity was re-validated using signal-to-noise, LOD was 0.025 μg∙mL-1, and LOQ was 0.075 μg∙mL-1. The precision for the method was %RSD = 1.51 %. The robustness for pH is 8.7 ± 0.1 units, and for temperature, it is 30 ± 5oC. In addition, the oxidative and photolytic degradation of omeprazole was studied. A sample of omeprazole degraded 17.65 ± 2.65 % after three minutes of exposure to hydrogen peroxide. Photolytic oxidation degraded the sample significantly by 40.25 ± 0.074 %.