The film begins in the depths of the schooner La Amistad, a slave-ship carrying captured West Africans into slavery. The film's protagonist, Sengbe Pieh, most known by his Spanish name, "Cinqué," painstakingly picks a nail out of the ship's structure and uses it to pick the lock on his shackles. Freeing a number of his companions, Cinqué initiates a rebellion on board the storm-tossed vessel. In the ensuing fighting, several Africans and most of the ship's Spanish crew are killed, but Cinqué saves two of the ship's officers, Ruiz and Montez, whom he believes can sail them back to Africa.
After six weeks have passed, the ship is running out of food and fresh water, and Cinqué is growing angry with Yamba who believes keeping the Spaniards alive is the only way to get back to Africa. During the night, they pass another vessel, carrying a group of wealthy English-speaking passengers having a dinner party on deck. The next day, they sight land. Unsure of their location, a group of African men takes one of the ship's boats to shore to fetch fresh water. While there, La Amistad is found by a military vessel bearing an American flag - the Spaniards have tricked the Africans by sailing directly for the United States.
Captured by the American Navy, the Amistad Africans are taken to a municipal jail in New Haven, Connecticut, where the ship's occupants, and a tearful Cinqué, are thrown into a grim dungeon, awaiting trial.
The film's focus now shifts to Washington, D.C., where a session in the House of Representatives introduces John Quincy Adams (Anthony Hopkins), the elderly former President and politician. While strolling in the gardens, Adams is introduced to two of the country's leading abolitionists; the elderly freed slave Theodore Joadson (Morgan Freeman) and Christian activist Mr. Tappan (Stellan Skarsgård), both of whom are leading shipping magnates in New England and co-proprietors of the pro-abolitionist newssheet "The Emancipator". The two have heard of the plight of the Amistad Africans and attempt to enlist Adams to help their cause. Adams, apparently verging on senility, refuses to help, claiming that he neither condemns nor condones slavery. News of the Amistad incident also reaches current President of the United States, Martin Van Buren (Nigel Hawthorne), who is bombarded with demands for compensation from the juvenile Spanish Head of State, Queen Isabella II of Spain (Anna Paquin). At a preliminary hearing in a district court, the Africans are charged with "insurrection on the high seas", and the case rapidly dissolves into conflicting claims of property ownership from the Kingdom of Spain, the United States, the surviving officers of La Amistad, and the officers of the naval vessel responsible for re-capturing the slave-ship. Aware that they cannot fight the case on moral grounds, the two abolitionists enlist the help of a young attorney specializing in property law; Roger Sherman Baldwin (Matthew McConaughey).
At the jail, Baldwin and the abolitionists, along with a nervous Professor of Linguistics, attempt to talk to the Amistad Africans, but neither side is able to understand anything the other party says. In the prison, events among the Africans are accelerating. Yamba, Cinqué's apparent rival for authority amongst the Africans, has converted to Christianity and is now resigned to his death, believing that execution will send them to a pleasant afterlife. The death of a young man provokes the Africans into a furious demonstration against the American authorities, screaming and chanting in their native languages as a prison riot threatens. As the hearings drag on, Baldwin and Joadson regularly walk round the city docks, counting numbers in the Mande language, in an attempt to recruit an interpreter. They eventually happen upon a black sailor in the Royal Navy, James Covey (Chiwetel Ejiofor).
Using Covey's linguistic abilities, Baldwin and his companions are able to talk to...