Most people grab whichever bottle is closest. That works fine most of the time. But there are situations where one of these is actually the better call, and a few where the others are genuinely a bad idea. Here’s the practical version.

What’s actually in the bottle

Three different drugs, marketed under names that don’t make this obvious:

• Tylenol is acetaminophen. Reduces pain and fever. Doesn’t touch inflammation.
• Advil and Motrin are both ibuprofen. Reduce pain, fever, AND inflammation.
• Aleve is naproxen. Same family as ibuprofen (called NSAIDs), but lasts longer per dose.

That last group — NSAIDs — also includes aspirin, though aspirin is mostly used these days for its blood-thinning effect rather than for everyday pain.

When to reach for which

Headache or fever. Either Tylenol or Advil works. This is mostly personal preference and what your stomach tolerates better. If you’re prone to heartburn or stomach issues, Tylenol is the gentler choice.

Sprained ankle, pulled muscle, sore back from yard work. Advil or Aleve. The inflammation is doing real work in the pain you’re feeling, and the NSAIDs go after that. Tylenol won’t help much here.

Menstrual cramps. NSAIDs, hands down. Cramps are driven by prostaglandins, the exact thing NSAIDs block. Take it at the first sign rather than waiting for the cramps to peak.

Arthritis pain. NSAIDs are typically more effective. There’s actually evidence that acetaminophen does not work well for low back pain or knee osteoarthritis, so for these specifically, ibuprofen or naproxen is a better bet.

Toothache or after dental work. Here’s a useful trick: ibuprofen 400 mg PLUS acetaminophen 500 mg, taken together, beats either alone — and beats most prescription opioids in head-to-head trials of dental pain. Different mechanisms, additive effect, no extra side effects.

Kid with a fever. Either acetaminophen or ibuprofen, dosed by weight (not age). Don’t give aspirin to anyone under 18 — it’s linked to a rare but serious condition called Reye syndrome. Use the syringe that comes with the medication, not a kitchen spoon.

When NOT to reach for them

NSAIDs (Advil, Aleve) are the ones with the longer warning list. Avoid or use sparingly if you have:

• Kidney disease (NSAIDs strain the kidneys further)
• Heart failure or high blood pressure that’s not well controlled
• A history of stomach ulcers or GI bleeding
• You’re on a blood thinner (warfarin, apixaban, etc.)
• You’re older than 65 — risks rise meaningfully
• You’re in the third trimester of pregnancy

Even in healthy people, NSAIDs carry a small but real increased risk of heart attack and stroke that goes up with higher doses and longer use. The boxed warning on every NSAID label is real. For occasional use over a few days, the risk is small. For daily use over weeks or months, it deserves a conversation with your doctor.

Acetaminophen has its own danger zone, just a different one — the liver. The catch is that acetaminophen is hidden in dozens of cold and flu products (NyQuil, Sudafed, DayQuil, Theraflu, Excedrin, many others), and it’s easy to accidentally double up. Adults shouldn’t exceed 3,000 to 4,000 mg per day total, and lower if you have liver issues or drink alcohol regularly. Always check the label.

A few practical tricks

Stagger them for stubborn pain. For something like a really bad headache or post-procedure pain, alternating Tylenol and ibuprofen (one, then the other 3 hours later) gives you steadier coverage than either alone. Same trick works for kids with stubborn fevers, though check timing with your pediatrician.

Take NSAIDs with food. Reduces the stomach irritation considerably. Tylenol is fine on an empty stomach.

Aleve = twice a day, Advil = every 6 hours. Aleve’s longer half-life means less pill-taking but also that any side effects stick around longer. If you’re trying naproxen for the first time, this is worth knowing.

Topical NSAIDs are underused. Voltaren gel (diclofenac) is now over the counter and works well for hand and knee arthritis pain with much less of the systemic risk that comes with the pill versions. Worth knowing about.

When over-the-counter isn’t enough

If you’re reaching for any of these more than a couple of times a week for ongoing pain, it’s worth a conversation with a doctor. Chronic pain has more options than over-the-counter pills, and most chronic pain is now treated with non-opioid medications (often combined with physical therapy and other approaches) rather than opioids as first-line.

For headaches that won’t respond to over-the-counter pain relievers, particularly recurring ones, it’s worth understanding when migraine-specific medications are the better answer.

The bottom line

For most everyday pain, all three work. The match between the type of pain and the medication matters more than people realize: NSAIDs for inflammation-driven pain, acetaminophen for fever and headaches when your stomach can’t handle NSAIDs, the combo of both for stubborn pain. Watch the hidden acetaminophen in cold medicines, watch the stomach and kidney effects of NSAIDs, and don’t make any of these a daily habit without checking with someone first.