Despite Nelson's fondness for the ship, Agememnon was frequently in need of repair and refitting, and would likely have been hulked or scrapped in 1802 had war with France not recommenced. She fought at the Battle of Trafalgar on 21 October 1805, as part of Nelson's weather column, where she forced the surrender of the Spanish four-decker Santissima Trinidad, later serving in South American waters off Brazil.
Her oft worn-out and poor condition contributed to her being wrecked when in June 1809 she grounded on an uncharted shoal in the mouth of the River Plate, whilst seeking shelter with the rest of her squadron from a storm. All hands and most of the ship's stores were saved, but the condition of the ship's timbers made it impossible to free the ship; her captain was cleared of responsibility for the ship's loss thanks to documents detailing her defects. Recently, the wreck of Agamemnon has been located, and several artefacts have been recovered, including one of her cannons.