Background Over 50 years ago, indomethacin emerged as an extremely potent non‐steroidal anti‐inflammatory drug (NSAID) during a massive effort to find effective anti‐inflammatory and analgesic medications. The 1960s saw acetic acid derivatives developed into indomethacin, diclofenac, and sulindac, and propionic derivatives into ibuprofen, naproxen, and ketoprofen. Indomethacin was likely the most potent of these compounds and one of the earliest to enter clinical trials. It is not surprising that indomethacin was among the first of the NSAID medications to be used in treatment of migraine and for headaches that eventually became known as “indomethacin‐responsive” headache disorders. Potential pharmacokinetic and bio‐mechanistic differences between indomethacin and other NSAIDs are of great clinical and research interest to explain this observation. Methods/Results The present article summarizes pharmacologic properties of indomethacin, including pharmacokinetics with particular attention to its distribution into the central nervous system, adverse effects, drug interactions, and mechanisms of action. Data are emphasized where differences in biomechanisms are found between indomethacin and other NSAIDs. The use of indomethacin in pregnant and lactating women is reviewed. Conclusions NSAIDs easily enter the brain, but their high protein binding limits absolute amount of entry. All work similarly as either nonselective or selective cyclooxygenase inhibitors, but indomethacin may have more potent vasoconstrictive activity and unique direct neuronal or nitric oxide‐dependent inhibitory pathway activity.