On the morning of September 11, 2001, the townsfolk of Gander (including Claude the mayor, Oz the police constable, Beulah the teacher, Bonnie the SPCA worker and others) describe life in Newfoundland and how they learn of the terrorist attacks taking place in New York City, Washington, D.C., and Shanksville, Pennsylvania ("Welcome to the Rock").

The attacks result in US airspace being closed, forcing 38 international aircraft to be diverted and land unexpectedly at the Gander airport, doubling the population of the small Newfoundland town, which is unequipped for the influx of stranded travelers ("38 Planes"). The Gander townspeople spring to action and prepare to house, feed, clothe, and comfort the nearly 7,000 passengers (along with 19 animals in cargo) ("Blankets and Bedding"). Meanwhile, the pilots, flight attendants and passengers are initially not permitted to leave the planes, forcing them to deal with confusing and conflicting information about what has happened and why they were suddenly grounded ("28 Hours / Wherever We Are").

Once allowed off the planes and transferred to various emergency shelters in and around Gander ("Darkness and Trees"), the passengers and crew watch replays of the attacks on the news and learn the true reason why they were grounded ("Lead Us Out of the Night"). The frightened and lonely passengers desperately try to contact their families and pray for their loved ones, while the townsfolk work through the night to help them in any and every way they can ("Phoning Home / Costume Party"). The travelers are initially taken aback by their hosts' uncommon hospitality, but they slowly let their guards down and begin to bond with the quirky townsfolk and each other. The "islanders" in Gander and the surrounding towns open up their homes to the "plane people", regardless of their guests' race, nationality or sexual orientation. Two women, Beulah (from Gander) and Hannah (from New York), bond over the fact that both of their sons are firefighters, but Hannah's son is missing ("I Am Here"). Hannah asks Beulah to take her to a Catholic church, and a number of characters make their way to other houses of worship around town ("Prayer").

To alleviate rising fear and mounting tensions ("On The Edge"), the passengers are invited to be initiated as honorary Newfoundlanders at the local bar ("Heave Away / Screech In"). The gravity of the attacks nevertheless continues to set in as US airspace is eventually reopened. One trailblazing pilot, Beverley Bass, comments on how her once optimistic view of the world has suddenly changed ("Me and the Sky"). While one pair of passengers starts to develop a romance despite the terrible thing that brought them together ("Stop the World"), another pair sees their long-term relationship fall apart under the stress of the event.

As the passengers and crew fly away to their homes, they joyously exchange stories of the immense kindness and generosity that was shown to them by the Newfoundland strangers in their time of need ("Somewhere in the Middle of Nowhere"), but not before a Muslim traveler, faced with increasing prejudice from his fellow passengers, undergoes a humiliating strip search prior to boarding. The townsfolk in Gander return to normal life, but comment on how empty their town now seems and how different the world now feels. The passengers and airline staff who return to the United States are faced with the horror of the attacks' aftermath—including Hannah, who learns that her firefighter son lost his life during the rescue efforts ("Something's Missing").

Ten years later, the crew and passengers (the "come from away") of the once stranded planes reunite in Gander, this time by choice, to celebrate the lifelong friendships and strong connections they formed in spite of the terrorist attacks ("Finale"). As Claude the mayor professes, "Tonight we honour what was lost, but we also commemorate what we found."