I'll vote for the largest loss of Union (& other) lives* during the war itself , not caused by combat - the burning and sinking of the transport
General Lyon on March 31st 1865. It's so overlooked that the article about overlooked events overlooked it.
*I exempt Sultana (never been overlooked) 1 day after Johnson surrendered, on the grounds that it was "after" the war - even though the war was not officially over until mid-1866. (And since failure to count April 1866 as an Easter Sunday 'during' the war didn't invalidate certain answers in a certain trivia contest which will remain unnamed, harrumph!)
With over 55o deaths - paroled soldiers, time-expired soldiers, Rebel prisoners, civilian men, women and children, merchant seamen including a would-be rescuer and one French-speaking capitalist dealing in blockade running . (His was a name well-known in New York even today, but omitted from the passenger lists in the NY Times.... one wonders why) - it's just a footnote, if even that.
This oversight will be partially corrected when my book on the
Lyon comes out (12th of Sometime-ber 20something).