Use caution: both Benadryl (diphenhydramine) and melatonin make you drowsy, so taking them together can pile on the sedation — an occasional combined dose isn't usually dangerous, but it's not the safe routine sleep fix it looks like, and you should check with a pharmacist first.
The concern is additive sedation, not a chemical reaction. MedlinePlus notes diphenhydramine (Benadryl) "may make you drowsy" and is itself used as a sleep aid in adults, while the NHS says "lots of medicines may increase or decrease the drowsy-making (sedating) effects of melatonin" and warns, "Do not take any herbal remedies that make you feel sleepy while taking melatonin," because they "can increase the sedating effects of your medicine and make you feel much more drowsy." Stacking two sedatives can mean deeper-than-expected drowsiness, dizziness, next-morning grogginess, and impaired driving. They also work against each other for sleep: melatonin nudges your natural sleep-wake cycle (NCCIH notes it "helps with the timing of your circadian rhythms"), whereas diphenhydramine is a blunt antihistamine sedative that isn't meant for nightly use.
Don't drive or operate machinery — MedlinePlus says not to drive until you know how diphenhydramine affects you, and the NHS says not to drive or operate machinery if melatonin makes you sleepy, dizzy, or unable to concentrate. Watch for excessive drowsiness, dizziness, confusion, and a "hangover" the next day; if those hit, separate or stop the combination. Keep diphenhydramine to the labeled dose (typically not more than every 4–6 hours) and melatonin low (a small dose is usually enough). Avoid alcohol and any other sedating drug — benzodiazepines, opioids, prescription sleep aids — on top of either one; the NHS specifically flags these as interacting with melatonin. Older adults should be especially careful: MedlinePlus says diphenhydramine generally should not be used in older adults. Don't use diphenhydramine as a regular sleep aid, and talk to a pharmacist or doctor before combining — particularly if you have glaucoma, an enlarged prostate or trouble urinating, or lung disease (emphysema, chronic bronchitis) per MedlinePlus, or if you have epilepsy or take blood thinners, which NCCIH says require medical supervision with melatonin. Also check first if you are pregnant, breastfeeding, or giving either to a child.
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.