Introduction: A common treatment for localized prostate cancer (PCa) is radiotherapy; however, effectiveness is hampered because of toxicities and tumor resistance. Cyclooxygenase-2 (COX-2) inhibitors have been identified as potential agents that could improve treatment outcomes and have demonstrated ability to increase the radiosensitivity of many human carcinomas. This retrospective human study aims to investigate the ability of COX-2 inhibitors, celecoxib, and meloxicam, to improve treatment outcomes after radiotherapy. Methods: Prostate Specific Antigen (PSA) data of eligible patients were obtained from Genesis Cancer Care, Southport, Australia. The primary outcome was the percentage of patients in each group that had reached biochemical relapse at two and five years after treatment. Secondary outcomes included time to biochemical relapse and PSA velocity. Results: At two and five years after treatment, both the celecoxib (6.7%, 18.3%) and meloxicam (0.0%, 18.9%) showed lower relapse rates than the control (8.6%, 31.0%). Although not statistically significant, these results are clinically significant. In addition, the two treatment groups were found to increase the time to relapse, 46.20 months for celecoxib and 54.15 months for meloxicam, compared with the control group, 35.53 months. A similar trend was shown for PSA velocity with both treatment groups demonstrating lower PSA velocities compared with control. Conclusions: This study provides further evidence to the potential for COX-2 inhibitors to address gaps in localizedz PCa treatment by demonstrating high clinical significance for the use of celecoxib and meloxicam. Further research should be conducted including larger retrospective studies and prospective studies to fully evaluate the benefits of COX-2 inhibitors in combination with radiotherapy for PCa.