This song is in a moderately fast 3/4 time, in the key of B flat major. The arrangement is based on rhythm chords played on acoustic piano, accompanied by bass, drums, and violin. The harmonic pattern consists of the chords I-VIIb-IV-I (Bb-Ab-Eb-Bb) throughout. The lyrics are all verses; there is no chorus. The melody is in the style of a modal folk song, emphasising the tonic and dominant notes in the scale, with leaps of a fifth in between them. The mode is Mixolydian with a major third in the harmony, but Dylan's delivery of the melody uses a flatted third as in the blues. The length of the track is 6 minutes and 58 seconds. The lineup: Bob Dylan, voice, piano and harmonica; Scarlet Rivera, violin; Rob Stoner, bass; Howie Wyeth, drums.
"Isis" tells a tale of a man who married an enigmatic figure named Isis. The main part of the story told by her spouse is about his separation from her. The song opens with their wedding "on the fifth day of May," an allusion to Cinco de Mayo, a patriotic holiday of Mexico, one of several Mexican themes found in Dylan's songs during the 1970s. Still in the first verse, the tale describes the couple's separation and the narrator's travels through an adventure that sounds like the Wild West or Mexico crossed with Egypt crossed with allegorical science fiction. He rides a pony and hitches it up "on the right" in a "high place" symbolically divided by a line through the middle into light and dark. He goes to wash his clothes, as though to wash himself of his past. He falls in with a shady character who promises easy treasure. They ride "to the pyramids all embedded in ice," and dig in freezing conditions until the treasure-hunting companion dies. So the narrator breaks into the empty tomb, finds no treasure, and realizes the adventure had been crazy. He buries the dead man in the tomb within the pyramid, says a quick prayer, and rides back to Isis because he still loves her. He sees her in a field where Isis asks him if he is going to stay this time. The narrator replies "If you want me to, yes!"
The song was written and recorded during a time of separation and reunion in Dylan's own marriage; consequently, for fans and critics the temptation to interpret it as an allegory of Dylan's own marital difficulties is irresistible, especially since the Desire album contains the song "Sara" which is openly about their marriage and separation. Since Dylan was known to include autobiographical hints in his previous songs, this interpretation cannot be considered farfetched. "Isis" draws upon mythological themes of a male hero separating from his wife, going on adventures, and returning to the marriage, going back to the Odyssey.
Dylan did an up-tempo live version of this song with the Rolling Thunder Revue, a performance of which was included in the film Renaldo and Clara. A live Rolling Thunder version of the song was included on the compilation album Biograph, which Dylan introduces as "a song about marriage". Coupled with the name of the album, this introduction further insinuates that the song documents Dylan's marital tribulations.