Most athletes experience musculoskeletal injuries during their sports activity that require rest at a minimum, and occasionally injuries are severe enough to necessitate surgical repair. Neurosurgeons are often consulted for athletically sustained injuries and prescribe medications for the associated pain. The use of both over-the-counter and prescription nonsteroidal medications is frequently recommended, but recent safety concerns must now be considered. The authors discuss the biochemical pathways of nonsteroidal drugs and review the potentially serious side effects of these medications. They also review the use of natural supplements, which may be a safer, and often as effective, alternative treatment for pain relief.