[12] Mefenamic acid is contraindicated in people who have shown hypersensitivity reactions such as urticaria and asthma to this drug or to other NSAIDs (e.g. aspirin); those with peptic ulcers or chronic inflammation of the gastrointestinal tract; those with kidney or liver disease; heart failure; after coronary artery bypass surgery; and during the third trimester of pregnancy.

Potentially serious side effects may include diarrhea, gastrointestinal perforation, peptic ulcers, hematemesis (vomiting blood), skin reactions (rashes, itching, swelling; in rare cases toxic epidermal necrolysis) and rarely blood cell disorders such as agranulocytosis.

[17][18] In its November 2023 monthly drug safety alert under the Pharmacovigilance Programme of India (PvPI), the Indian Pharmacopoeia Commission flagged a risk of DRESS Syndrome due to use of mefenamic acid.

[19] Symptoms of overdosing include kidney failure, gastrointestinal problems, bleeding, rashes, confusion, hallucinations, vertigo, seizures, and loss of consciousness.

Combination with antihypertensive drugs such as ACE inhibitors, sartans and diuretics can decrease their effectiveness as well as increase the risk for kidney toxicity.

This prevents formation of prostaglandins,[15][20] which play a role in pain sensitivity, inflammation and fever, but also in hemostasis, kidney function, sustaining of pregnancy, and protection of the gastric mucosa.

[21] Mefenamic acid is rapidly absorbed from the gut and reaches highest concentrations in the blood plasma after one to four hours.

Specifically, the arrangement of the substituted benzene fragments relative to each other plays a crucial role in determining the different polymorphic forms of mefenamic acid.

External factors, including temperature, pressure, and the surrounding medium, highly influence the conformational state of mefenamic acid.

Researchers have conducted extensive investigations into its spatial structure not only in organic solvents[28] but also in supercritical fluids,[29][30] aerogels,[31] and lipid bilayers.

[39][40][41] A small controlled study of 28 human subjects showed improved cognitive impairment using mefenamic acid non-steroidal anti-inflammatory therapy.