The Dante Club begins with the murder of fictional Massachusetts Chief Justice Artemus Healey, who had avoided taking a position to stop or support the escaped slaves of the South.

Found by his chambermaid near a white flag atop a short wooden staff, Healey had been hit in the head and then left in his garden to be eaten alive by strategically placed maggots and stung by hornets.

The club, including Henry Wadsworth Longfellow, Oliver Wendell Holmes Sr., and James Russell Lowell, sets out to solve the murders, fearing that the truth will ruin Dante's burgeoning reputation in America, thus making their translation a failure, as well as the obvious problem that they would be virtually the only suspects if they reported this information to the police.

Then, Phineas Jennison, both a wealthy contributor to the Harvard Corporation and friend to the translators (a "schismatic"), is sliced open exactly down the middle—all killed in extreme fashion and undeniable resemblance to the punishments of people in Dante's Inferno.

The club eventually tries to capture him, with the aid of Boston's first African-American policeman Nicholas Rey, the only other person who saw the connection, while he is attempting to punish Harvard Treasurer Dr. Manning and Pliny Mead ("the traitors").