The song has five stanzas. In each stanza, someone describes an unusual problem that is ultimately resolved on Highway 61. In Verse 1, God tells Abraham to "kill me a son". God wants the killing done on Highway 61. This stanza refers to Genesis 22, in which God commands Abraham to kill one of his two sons, Isaac. Abram, the original name of the biblical Abraham, is the name of Dylan's own father. Verse 2 describes a poor fellow, Georgia Sam, who is beyond the helping of the welfare department. He is told to go down Highway 61. Georgia Sam may be a reference to Piedmont blues musician Blind Willie McTell, who occasionally went by Georgia Sam when recording.