At the beginning of Twain's "The Invalid's Story,'' the narrator explains that he looks and feels older than he is and that he used to be much healthier than he is now. He attributes his decline in health to the strange events of one winter night, in which he traveled with a box of guns for two hundred miles.

The narrator recalls how, two years before, he had arrived at his home in Cleveland, Ohio and learned of the recent death of his friend, John B. Hackett. Following Hackett' s last wishes, the narrator leaves for the train station to take Hackett's body back to his parents in Bethlehem, Wisconsin.

The narrator finds a white-pine box at the train station that matches the description of the coffin. He attaches the address card from Hackett's father, Deacon Levi Hackett, to the white-pine box, and has it loaded into the train on the express car—a method for transporting packages by train that was safer and faster, but more expensive, than normal freight cars.

The narrator leaves to get food and cigars, and when he comes back to the area where he had first found the white-pine box, a young man is tacking an address card onto an identical box.

The narrator checks to make sure his white-pine box is still in the express car, which it is. At this point, the narrator lets the reader know that the boxes are labeled wrong. The first box, the one in the express car, which the narrator assumes is the corpse of his friend, is actually a box of guns that is meant to go to Peoria, Illinois. Conversely, the second box, which the young man assumes contains the guns, actually contains John Hackett's corpse.

However, the narrator is not aware of this fact at the time that he is taking the train trip. He settles into the express car, where he and the expressman— the man hired by the express company to look after the express packages—settle in for the long, two-hundred-mile journey. Right before the train takes off, a stranger comes into the express car for a moment and places a package of ripe Limburger cheese on top of the white-pine box. Just as neither the narrator nor expressman, a man named Thompson, are aware that the coffin box contains guns, they also don't realize that the package on top of the box contains ripe cheese. Once again, the narrator tells the reader this fact, but he does not know it at the time of the train trip.

As Thompson starts to seal the car against the winter storm that rages outside so that he and the narrator can keep warm, the ripe cheese also starts to get warm, and begins to smell. The narrator notices it first, and mistakes it for Hackett' s corpse, which he believes is starting to rot. Thompson starts a fire to help the two keep warm, which only makes the cheese stink even more. Although he is cheerful at the beginning of the trip, singing happy songs, Thompson eventually becomes aware of the cheese stench, and he stops his singing.

Thompson also assumes that the stench is from a rotting corpse, and he and the narrator begin to talk about it. Thompson notes the smell of the corpse and says that he has transported people who were not really dead, only in a trance, but that he can tell by the stench that the narrator's friend is not one of these.

In an effort to get away from the smell, Thompson breaks one of the express car's window panes and sticks his nose outside to get some fresh air. He and the narrator take turns sniffing at the window, and Thompson asks how long the narrator's friend has been dead. Thompson does not believe the narrator's assertion that Hackett died recently, because a corpse could not rot and produce such a pronounced smell in a few days. Thompson admonishes the narrator, saying that Hackett's body should have been laid to rest long ago. Meanwhile, the smell of the cheese has gotten so bad that the narrator suggests smoking cigars to try to mask the odor.

The cigars are the first of many failed attempts to try to tame the smell of the cheese. After the cigars fail, Thompson suggests that they move the box to the other end of the express car. This does not work and the two run outside onto the express car's platform to get some fresh air, where they discuss their predicament. They can not stay outside or they will freeze to death in the stormy winter weather, but they can not handle the smell either. They end up going back inside the car, once again taking turns getting air at the window.

When the train pulls away from the next train station, Thompson comes back into the express car with carbolic acid, a caustic, poisonous chemical commonly used as a disinfectant. He douses the box and cheese with the acid, but it is no use; the acid only adds a new odor, while magnifying the first one. After they leave the next train station, Thompson tries again, this time by starting a bonfire of chicken feathers, dried apples, sulphur, and other items.

The resulting smell is so bad that Thompson and the narrator resolve to spend the rest of the trip out on the platform, even though it will probably mean their death from typhoid fever. An hour later at the next train station, the frozen expressman and narrator are removed, and the narrator is violently ill for three weeks. It is at this point that he finds out about the box of guns and the ripe cheese. At the end of the story, the narrator, once again in the present, explains that the fateful trip sapped his health, and that he is going home to die.