In this song, Dylan mixes lyrics of his own with lyrics from old Blues songs by the likes of Charlie Patton, Brownie McGhee and Leroy Carr. At face value, it seems to be expressing a sense of world-weariness, but some fans argue that, if you look hard enough, you will discover that it is actually about sexual frustration and is full of innuendo!
The title is suggesting life is fundamentally sad. While it takes a lot to make us laugh, it takes something as simple and as mundane as a train (and its consequent associations, such as lovers leaving town) to make us cry.
There is an alternative version of this song called "Phantom Engineer." It is faster, and has slightly different lyrics. It can be found on The Bootleg Series Volumes 1–3.
On July 25, 1965, Dylan performed this song at Newport Folk Festival as part of his controversial electric set. The folk fans in the crowd were angry that Dylan was playing with an amplified band at a strictly acoustic festival and booed throughout the performance. Dylan would not return to the festival until 2002.
Steely Dan took the title of their 1972 debut album, Can't Buy a Thrill from this song's opening lines: "Well, I ride on a mailtrain, baby, can't buy a thrill." Walter Becker of Steely Dan told Mojo magazine that he'd never met Dylan, but agreed with actor Jack Nicholson's comment "to the effect that, as long as he is alive, Bob Dylan will be the greatest living songwriter."
Highway 61 Revisited is named after US Route 61, which connects Dylan's birthplace in Minnesota to southern cities such as St. Louis, Memphis, and New Orleans - all of which are famed for their musical heritage.