The lyrics appear to relate the story of a man pleading with a woman to let him in her house; the speaker calls himself "Papa McTell" in the first stanza ("Have you got the nerve to drive Papa McTell from your door?"). Throughout the song, the woman, addressed as "mama," is alternately pleaded with (to go with the speaker "up the country") and threatened ("When I leave this time, pretty mama, I'm going away to stay"). Throughout the non-linear narrative, the "Statesboro blues" are invoked—an unexplained condition from which the speaker and his entire family seem to be suffering ("I woke up this morning / Had them Statesboro blues / I looked over in the corner: grandma and grandpa had 'em too"). Later versions, such as the one by the Allman Brothers Band, have shorter, simplified lyrics.
As with many blues lyrics, it can be difficult to establish a definitive narrative order for the stanzas. In the case of "Statesboro Blues," Richard Blaustein attempted a structural analysis of McTell's song in an approach influenced by Claude Lévi-Strauss; it is unclear whether his results are applicable to other blues songs.
In 2016, the song was selected for preservation in the National Recording Registry due to its "cultural, historic, or artistic significance". It is included on several compilations of McTell's recordings.