Proton-pump inhibitors (PPIs) are often co prescribed with non-steroidal anti-inflammatory drugs (NSAIDs) to reduce the latter induced gastrointestinal adverse effects. A patent for dosage forms containing a PPI, NSAID, and buffer was approved to allow patients receive a simpler treatment regimen at lower cost, and take the benefits of NSAID therapy without experiencing its undesirable side effects. A precise and accurate high-performance liquid chromatographic (HPLC) method has been developed and validated for simultaneous determination of a PPI (pantoprazole, PAN) and piroxicam (PIR) as an NSAID in prepared tablets, capsules, and in pharmaceutical formulations. Optimum chromatographic separation of PAN and PIR was achieved using response surface methodology (RSM). Analysis was performed on ODS-3 Inertsil C18 column (250 mm × 4.6 mm i.d., 5 μm), with an isocratic mobile phase consisting of acetonitrile and 48.09 mM phosphate buffer (pH 4.92) (53.61:46.39, v/v) at a flow rate of 1.0 mL/min and ambient temperature using photo diode array (PDA) detector at 220 nm. The retention time of PAN and PIR were 4.217 and 6.249 min, respectively. The developed method was linear over the ranges of 5.0–30 µg/mL for PAN and 2.5–15 µg/mL for PIR. The current developed method can be successfully used for simultaneous determination of PAN and PIR in quality control laboratories where expensive equipments are not available.