In 1781, Ichabod Crane works for George Washington as a double agent. Crane beheads a Horseman, who does not die. In desperation, Crane kills him with a mutually fatal blow. Crane next awakens in 2013 Sleepy Hollow, with Washington's Bible to guide him. He meets Sheriff's Lt. Abigail Mills and learns that the Horseman has also returned. Crane learns that he and Abbie are the two Witnesses of Revelation, and the Horseman is Death. Should he regain his severed head, his master, Moloch, would be released from Purgatory and the End of Days would occur. Crane also learns that his wife, Katrina, a witch, was banished to Purgatory for saving him. His blunder has linked his life with the Horseman's. Fighting off Moloch's army of demons, Crane discovers that the Horseman of War is his own son, Jeremy Crane/Henry Parish, who loathes Crane and Katrina for abandoning him. Crane also learns that "Headless" is actually his former friend, Abraham Von Brunt.

Crane and Abbie manage to defeat Moloch, but at the cost of releasing everything trapped in Purgatory, including demons looking for a replacement for Moloch. Henry convinces Katrina to side with him and awaken the descendants of their coven, but both are killed by Crane, who is filled with regret and remorse.

In the following months, Crane investigates all myths about the Witnesses, learning that Moloch was the first of Seven Tribulations. The second comes in the form of Pandora and her master, the Hidden One, an ancient Sumerian god. Because Moloch is dead (and thus cannot end the world), Crane gives the Horseman back his head, allowing him to destroy Pandora. However, the head is sucked into Pandora's box, which is destroyed. This battle costs Abigail her soul. Learning that there will always be two Witnesses, Crane vows to find her replacement and face the last five Tribulations.

Relocating to Washington D.C., Crane discovers that the next Witness is a young girl named Molly. Crane works with her mother, Agent Diana Thomas of Homeland Security, to combat supernatural threats until Molly is old enough to help. Crane also allies with Agency 355 agents Jake Wells and Alex Norwood, taking command of the organization as George Washington wished.

The third tribulation comes in the form of Malcolm Dreyfuss, who sold his soul to build his business. Dreyfuss seeks immortality for he fears death. After Dreyfuss becomes immortal, he decides to assemble the Four Horsemen, kill the President and take over the United States of America. A woman named Lara arrives from the future that Dreyfuss wishes to create, revealing herself to be an alternate version of young Molly. Because she is in her prime, Lara takes the Witness title from Molly, releasing her past self from the burden. Crane is forced to make a deal with the devil for a piece of the philosophers' stone that will strip Dreyfuss of his immortality and send him to Hell.

While Lara goes on a journey to discover her place in the world, Crane continues working with Agent Thomas to combat supernatural threats, hoping that he can someday escape his bargain with the devil.