Ned Flanders becomes frustrated when Homer disrupts his Bible study group, and Reverend Lovejoy recommends that Ned invites the Simpson family to join the group on their tour of Jerusalem. Homer is skeptical, but Marge accepts and soon the family is on their way to Israel. Upon arrival in Jerusalem, they are joined by Krusty the Clown, who is making a Jewish pilgrimage. They pass the Western Wall and meet a talkative and pushy tour guide named Jakob.
At first, Homer and the other tourists show more interest in the hotel's buffet than they do in seeing the city, much to Ned's dismay. When they arrive at King David's tomb, Ned implores Homer to show some respect. Homer, however, continues to goof off and Ned becomes increasingly impatient with him.
Their next stop is the Church of the Holy Sepulchre, where Ned prays that Homer finds some meaning in the tour. But when he discovers Homer taking a nap on Jesus' tomb, he loses his temper and yells at Homer. Ned is removed from the church by security and is banned for life from visiting the site. Ned subsequently scolds Homer, telling him that his soul is "not worth saving", and storms off. Homer rushes after Ned to make amends, but loses sight of him and believes that Ned is lost in the desert, while Ned merely went to get a cup of tea to calm his anger, after which he went to see a movie. Homer takes a camel and rides off to find Ned, but soon becomes lost in a sandstorm and starts to feel the effects of dehydration. Homer arrives at the Dead Sea and drinks some of the salty water, furthering his dehydrating. He hallucinates a visit from a pickle, carrot, and tomato from VeggieTales, who tell him that he is the new Messiah.
After Homer is rescued by Marge and a security guard, Dr. Hibbert diagnoses him with Jerusalem syndrome, whose sufferers possess religiously-themed obsessive ideas. Homer escapes from the hotel and ends up at the Dome of the Rock. Marge, the Simpson children, and Dr. Hibbert chase after him, only to hear him preach that the similarities of different religions outweigh their differences, and that all should search for a common ground for a joint new religion, the so-called "Chrismujews". Ned witnesses Homer's speech and is profoundly moved, but the effect is lost on the crowd as nearly all of the other tour group members have developed Jerusalem syndrome as well. On the flight back to Springfield, Ned and Homer reconcile.