Usually not a good idea to combine: NyQuil already contains a sedating antihistamine (doxylamine), so adding Benadryl (diphenhydramine) stacks two of the same drug class and piles on drowsiness — check with a pharmacist before mixing them.
Benadryl's active ingredient is diphenhydramine, a "drowsy" (sedating) antihistamine, and nighttime NyQuil already contains doxylamine succinate (12.5 mg per dose) — a second sedating antihistamine — alongside dextromethorphan and 650 mg of acetaminophen. The NHS warns to check with a pharmacist or doctor before taking diphenhydramine with "any other antihistamines" or "any other medicine that makes you drowsy, gives you a dry mouth, or makes it difficult for you to pee," because the sedating and drying (anticholinergic) effects add up. The FDA NyQuil label itself flags that "marked drowsiness may occur" and says to ask a doctor or pharmacist first if you also take sedatives or tranquilizers. So the danger here isn't acetaminophen (plain Benadryl contains none) — it's two antihistamines stacking excess sedation and anticholinergic load, not a clearly safe pairing.
The main risk is over-sedation: heavy drowsiness, dizziness, unsteadiness, trouble concentrating, dry mouth, blurred vision, constipation, or trouble urinating — and at higher combined doses, confusion or a fast heartbeat. Do not drive or operate machinery, and do not drink alcohol — the NHS warns that alcohol and diphenhydramine together can make you sleep so deeply that you cannot breathe properly and may have difficulty waking up. Older adults are especially vulnerable — MedlinePlus says diphenhydramine generally should not be used in older adults, except to manage serious allergic reactions. Also read NyQuil's label: never combine it with another product containing acetaminophen, and stay within the dosing limits (severe liver damage can occur above the 4-doses-in-24-hours daily maximum). If you only want NyQuil's antihistamine effect, you usually don't need to add Benadryl at all. Ask a pharmacist before combining, and seek urgent care for extreme sleepiness, breathing trouble, confusion, or a racing heart.
This is general reference, not medical advice, and not a guarantee of safety. Interactions depend on your doses, health conditions, and other medicines. Always confirm with your pharmacist or doctor before combining products, and follow the dosing on each label.