Unlike most of Canned Heat's songs from the period which were sung by Bob Hite, second guitarist and harmonica player Alan Wilson provides the distinctive high pitched vocal, sometimes described as a falsetto.

An edited version was released as a single in April 1968 on the Liberty label and became Canned Heat's first record chart hit and one of their best-known songs.

In "Dark Road" (1951), Jones "reshaped Tommy Johnson's verses into an eerie evocation of the Delta":[6] Whoaa well my mother died and left me Ohh when I was quite young, when I was quite young ... Said Lord have mercy ooo, on my wicked son Jones later remade "Dark Road" with the title "On the Road Again"[6] and added: Whoaa I had to travel, whoaa in the rain and snow in the rain and snow My baby had quit me ooo (2×) Have no place to go Both songs share a "hypnotic one-chord drone piece"-arrangement that one-time Floyd Jones musical partner Howlin' Wolf used for his songs "Crying at Daybreak" and the related "Smokestack Lightning".

[6][7] "On the Road Again" was among the first songs Canned Heat recorded as demos in April 1967 at the RCA Studios in Chicago[8] with original drummer Frank Cook.

Although Bob Hite was the group's primary vocalist, "On the Road" features Wilson as the singer, "utilizing his best Skip James-inspired falsetto vocal".

Although songs inspired by John Lee Hooker's "Detroit-era boogie"[3] had been recorded over the years by a variety of blues musicians, Canned Heat's "On the Road Again" popularized the guitar-boogie or E/G/A riff in the rock world.