The Good Lord Bird centers around the main character, Henry Shackleford, who travels with a fictionalized version of the Civil War Era John Brown, an anti-slavery fighter who had his famous stand at Harper's Ferry in Virginia. John Brown and his group believe that Shackleford is a girl.

Henry says that:

The Old Man heard Pa say 'Henry ain't a,' and took it to be 'Henrietta,' which is how the Old Man's mind worked. Whatever he believed, he believed. It didn't matter to him whether it was really true or not. He just changed the truth till it fit him. He was a real white man.

John Brown is a controversial figure which the author doesn't shy away from. He was anti-slavery but also believed that only violent insurrection could free the slaves. His famous stand at Harper's Ferry was an attempt to make that happen for reality. The author includes rumors about John Brown, such as:

Old John Brown and his murderous sons planned to deaden every man, woman, and child on the prairie. Old John Brown stole horses. Old John Brown burned homesteads. Old John Brown raped women and hacked off heads. Old John Brown done this, and old John Brown done that, and why, by God, by the time they was done with him, Old John Brown sounded like the most onerous, murderous, low-down son of a bitch you ever saw.

Henry, however, sees them differently. Of John Brown, he says:

It was the first time I ever saw him smile free. A true smile. It was like looking at the face of God. And I knowed then, for the first time, that him being the person to lead the colored to freedom weren't no lunacy. It was something he knowed true inside him. I saw it clear for the first time. I knowed then, too, that he knowed what I was - from the very first.

As Little Onion, he travels with "nothing but a ragtag assortment of fifteen of the scrawniest, bummiest, saddest-looking individuals you ever saw." They're known as the Pottawatomie Rifles and they don't see beneath Henry's disguise to the man underneath. They only see what they want to see.

Brown is kind to Henry and regards him -- Henrietta to Brown -- as his good luck charm. However, life with the Pottawatomie Rifles is a hardship in many ways. They have adventures but the group isn't good at managing itself or taking care of its members. Ultimately, Brown, like his real-life counterpart, makes his stand at Harper's Ferry and is overthrown and sentenced to die.

James McBride writes that:

Some things in this world just ain't mean to be, not in the times we want 'em to, and the heart has to hold it in this world as a remembrance, a promise for the world that's to come. There's a prize at the end of all of it, but still, that's a heavy load to bear.

Ultimately the institution of slavery that Brown and the Pottawatomie Rifles hated so much would be ended in the United States. Brown, however, would die before he saw it happen with the passage of the Thirteenth Amendment.