Hamilton was a principal in 11 affairs of honor: with the Rev. William Gordon (1779), Aedanus Burke (1790), John Francis Mercer (1792-1793), James Nicholson (1795), Maturin Livingston (1795-1796), James Monroe (1797), John Adams (1800), Ebenezer Purdy/George Clinton (1804), and Aaron Burr (1804).

Hamilton was secondarily involved in three duels, not counted among these 11: as a second to John Laurens in his duel with General Charles Lee (1779), as a second to legal client John Auldjo in his duel with federal Convention delegate William Pierce (1787) and as unofficial advisor to his son Philip before the latters duel with George Eacker (1801). (Joanne B. Freeman, William and Mary Quarterly, no. 2 , April 1996).

Hamilton had called Burr a "profligate" and "a voluptuary in the extreme." Their duel occurred on the morning of July 11, 1804, at Weehawken. Hamilton was mortally wounded, and like his son Philip in 1801, died the next day.