La Amistad is a slave ship transporting captured Africans from Cuba to the United States in 1839. Joseph Cinqué, a leader of the Africans, leads a mutiny and takes over the ship. The mutineers spare the lives of two Spanish navigators to help them sail the ship back to Africa. Instead, the navigators misdirect the Africans and sail directly north to the east coast of the United States, where the ship is stopped by the American Navy, and the surviving Africans imprisoned as runaway slaves.

In an unfamiliar country and not speaking a single word of English, the Africans find themselves in a legal battle. United States Attorney William S. Holabird brings charges of piracy and murder. Secretary of State John Forsyth, on behalf of President Martin Van Buren (who is campaigning for re-election), represents the claim of the Spanish government[a] that the Africans are property of Spain based on a treaty. Two Naval officers, Thomas R. Gedney, and Richard W. Meade, claim them as salvage while the two Spanish navigators, Pedro Montez and Jose Ruiz, produce proof of purchase. A lawyer named Roger Sherman Baldwin, hired by the abolitionist Lewis Tappan and his black associate Theodore Joadson, decides to defend the Africans.

Baldwin argues that the Africans had been captured in Africa to be sold in the Americas illegally. Baldwin proves through documents found hidden aboard La Amistad that the African people were initially cargo belonging to a Portuguese slave ship, the Tecora. Therefore, the Africans were free citizens of another country and not slaves at all. In light of this evidence, the staff of President Van Buren has the judge presiding over the case replaced by Judge Coglin, who is younger and believed to be impressionable and easily influenced. Consequently, seeking to make the case more personal, on the advice of former American president (and lawyer) John Quincy Adams, Baldwin and Joadson find James Covey, a former slave who speaks both Mende and English. Cinque tells his story at trial: Cinque was kidnapped by slave traders outside his village, and held in the slave fortress of Lomboko, where thousands of captives were held under heavy guard. Cinque and many others were then sold to the Tecora, where they were held in the brig of the ship. The captives were beaten and whipped, and at times, were given so little food that they had to eat the food from each other’s faces. One day, fifty captives were thrown overboard. Later on, the ship arrived in Havana, Cuba. Those captives that were not sold at auction were handed over to La Amistad.

United States Attorney Holabird attacks Cinqué’s “tale” of being captured and kept in the slave fortress, and especially questions the throwing of precious cargo overboard. Holabird contends that Cinque could have been made a debt slave by his fellow Sierra Leoneans. However, the Royal Navy’s fervent abolitionist Captain Fitzgerald of the West Africa Squadron backs up Cinqué’s account. Baldwin shows from the Tecora’s inventory that the number of African people taken as slaves was reduced by fifty. Fitzgerald explains that some slave ships when interdicted do this to get rid of the evidence for their crime. But in the Tecora’s case, they had underestimated the amount of provisions necessary for their journey. As the tension rises, Cinqué stands up from his seat and repeatedly says, “Give us, us free!”

Judge Coglin rules in favor of the Africans. After pressure from Senator John C. Calhoun of South Carolina on President Van Buren, the case is appealed to the Supreme Court. Despite refusing to help when the case was initially presented, Adams agrees to assist with the case. At the Supreme Court, he makes an impassioned and eloquent plea for their release, and is successful.

The Lomboko slave fortress is liberated by the Royal Marines under the command of Captain Fitzgerald. After all the slaves are removed from the fortress, Fitzgerald orders the ship’s cannon to destroy it. He then dictates a letter to Forsyth saying that he was right — the slave fortress doesn’t exist.

Because of the release of the Africans, Van Buren loses his re-election campaign, and tension builds between the North and the South, which eventually culminate in the Civil War.