In which battle did the most Americans die? The question is answered in the following lecture:

[Camaromjr]

13. One Day - September 17th, 1862

Total American deaths were ~4,000 at Antietam (~3,700 plus later deaths). It should also be noted that deaths during the Civil War were mostly dead on the battlefield or shortly there after. The state of medicine (Civil War medicine prescribed mercury for some stomach ailments) was appalling.

Gettysburg had over 10,000 dead with another 10,000 missing in the 3 days of July 1-3, 1863. There was over 51,000 total casualties.

Both of these are considered campaigns. The Maryland Campaign of 1862 would have included battles at South Mountain and others. The Gettysburg Campaign included the fighting at Brandy Station (JEB Stewart took it on the chin there) as well as several other battles in the valley.