The book features the Belgian detective Hercule Poirot. The action takes place in Egypt, mostly on the Nile River.

Linnet Doyle and her husband, Simon Doyle are in Egypt to celebrate their honeymoon. Simon Doyle was once engaged to Linnet's best friend, Jacqueline De Bellefort. The Doyles board the S.S. Karnak for a trip along the Nile River along with many other passengers. They are novelist Salome Otterbourne and her daughter, Rosalie; Mrs. Allerton and her son, Tim; Linnet's American lawyer and trustee Andrew Pennington; Linnet's maid Louise Bourget; American socialite Miss Van Schuyler and her niece Cornelia Robson; Miss Schuyler's nurse Miss Bowers; a mysterious man named Mr. Ferguson; the archeologist Signor Richetti; the silent man James Fanthorp; the Austrian Dr. Bessner; and Jacqueline De Bellefort. Also on board is the detective Hercule Poirot.

Jacqueline has been stalking Linnet and Simon since they were married, which has made them very angry. One night, Jacqueline De Bellefort tells Poirot she wants to kill Linnet and Simon. The day before, when everyone was visiting an Egyptian ruin, a boulder nearly fell on Linnet's head, but luckily it missed. Poirot, Linnet and Simon think Jacqueline is to blame, but they later find out she was on the boat the whole time and could not have done it. Poirot meets his friend Colonel Race, who is joining everyone on the boat for the return trip. Race tells Poirot that one of the passengers is a deadly criminal who has murdered many people before. That night on the boat, Jacqueline gets into a drunken rage, takes out a pistol, and shoots Simon in the leg. Simon insists that Jacqueline be cared for before him, and so the other two people present, Cornelia Robson and Fanthorp, take her back to her cabin. They call Dr. Bessner, who tends to Simon (who has also opened the window) and stays with him all night. Nurse Bowers stays with Jacqueline all night. Later, Fanthorp tells Bessner the gun is missing.

The next day, Linnet is found dead with a bullet in her head. When Poirot investigates, he finds a big "J" on the wall. Later, Poirot notices two bottles of nail polish in Linnet's room. One of the nail polish bottles is labeled "Cardinal", a deep, dark red. The other bottle was labeled "Rose", which is a shade of pale pink, but the few drops remaining in the bottle were not pale pink, but a bright red paint. He also sees Linnet's pearls are missing. Poirot then interviews all the passengers. He finds many of them heard a splash and someone running during the night. Miss Van Schuyler tells them that she heard a splash and saw Rosalie Otterbourne throw something into the water. Rosalie says she never left her cabin and didn't throw anything overboard. Louise Bourget tells Poirot how she might have seen the murderer if she had done certain things, which makes him suspicious. Poirot concludes that, despite being the prime suspect, Jacqueline could not have killed Linnet since she was accounted for all night. Poirot thinks someone saw Jacqueline shoot Simon, and used that opportunity to kill Linnet and frame Jacqueline. The gun is found overboard, which confuses Poirot, since if someone was trying to incriminate Jacqueline they would have left her gun in the cabin.

Slowly, Poirot begins to deduce what happened during the night. He realises that Rosalie was actually throwing some of her alcoholic mother's stash of drink overboard. He suspects Rosalie saw someone leave Linnet's cabin, but she says she did not. During lunch, Race tells the passengers that everyone will be searched in order to find the missing pearls. Nurse Bowers gives the pearls back, and tells Poirot Miss Van Schuyler took them, because she is a kleptomaniac. However the pearls are soon found to be fake. Louise Bourget is found murdered in her cabin holding on to some money, and it is deduced she was trying to blackmail the murderer. Poirot and Race enter Dr. Besser's cabin and tell the doctor and Simon what happened. Salome Otterbourne enters and says she knows who killed Linnet and Louise. Simon yells at her to tell him. Before she can finish her story, she is shot from behind and killed. Almost everyone on board comes to the cabin to see what the noise was, with Tim being the first to arrive. Poirot recognises the dropped gun as Andrew Pennington's, who is not in attendance. Poirot asks to meet with Pennington in an hour but first he meets with Tim. Poirot reveals it was Tim who stole the pearls. Tim had an accomplice in England make a fake copy of the pearls and switched them when he stole the real ones. Tim does not know if Linnet was already dead when he did this, although he does not remember her breathing. It was Tim who Rosalie saw, but Rosalie did not tell anybody because she thought they would suspect Tim of being the murderer and she has come to love him. Poirot says he will not tell the police that Tim stole the pearls, and lets him marry Rosalie.

When Poirot meets with Pennington, it is revealed that Pennington stole some of Linnet's money, and was trying to get Linnet to sign papers to free Pennington of any crime. Pennington found that Linnet reads papers in such detail that she might find out what Pennington did. Pennington learned that Simon does not read legal papers at all, and just signs them. Pennington tried to kill Linnet with the boulder so that he could deal with Simon instead, but was unsuccessful. But Pennington tells Poirot he did not shoot Linnet, and Poirot agrees with him. Further revelations are also made. Fanthorp is revealed to be from a law firm that suspected Pennington of his crimes, and came on the boat so that Linnet would not sign the papers (earlier he had distracted Linnet's attention just as she was about to sign them). Mr. Richetti is revealed to be the criminal Race is after, after Race hears of a telegram Richetti received filled with code words giving Richetti instructions.

Poirot tells Race he pretty much knew how the murder was actually committed earlier, but wanted to deal with other issues like the pearls and the boulder before he told anyone. Finally, he tells Race, Miss Robson, and Dr. Bessner about the murderers. His whole theory about someone overhearing the confrontation was false, which is why he could not figure out the truth for a while. Jacqueline and Simon were in it together. Jacqueline pretended to shoot Simon, and then while everyone was preoccupied with getting Jacqueline back to her cabin, because of the insistence of Simon, he took the gun, shot Linnet, then shot himself in the leg, and threw the gun overboard before anyone came back. When Dr. Bessner examined him, it appeared he was really shot by Jacqueline. He had used some fake blood earlier, and disposed of it in the nail polish bottle in Linnet's room. Simon got the hint Louise gave about knowing the murderer, and sent Jacqueline to kill her. When Mrs. Otterbourne told Simon she knew the murderer, Simon yelled for her to start at the beginning to give Jacqueline enough time to overhear him, get the gun, kill Mrs. Otterbourne and return to her cabin. Simon and Jacqueline were planning to marry, as they both were still in love, and they would live a life of luxury together with Linnet's money. Jacqueline tells Poirot that the murder was Simon's idea but she planned it, knowing Simon was not smart enough to pull it off by himself. As everyone is leaving the ship, Jacqueline takes a second pistol which she hid in Rosalie Otterbourne's and kills both Simon and herself. Miss Robson accepts Dr. Bessner's proposal of marriage, to the dismay of Mr. Ferguson, who had been courting her the whole trip.

The Times Literary Supplement's short review of November 20, 1937 by Caldwell Harpur concluded, "Hercule Poirot, as usual, digs out a truth so unforeseen that it would be unfair for a reviewer to hint at it".

In The New York Times Book Review for February 6, 1938, Isaac Anderson concluded after summarising the set-up of the plot that, "You have the right to expect great things of such a combination [of Agatha Christie and Hercule Poirot] and you will not be disappointed.".

In The Observer's issue of November 14, 1937, "Torquemada" (Edward Powys Mathers) started off by saying, "First this week comes Agatha Christie. She scored, I contend, two outers in her last three shots; but she is back on the very centre of the bull with Death on the Nile." He summarised the set-up of the plot and then continued, "Terrible things happen and, without the formality of breaking off her narrative to issue a challenge, the author allows Poirot to summarise his clues in one compressed paragraph sixty pages from the end. It is after that, until the retired but by no means retiring little Belgian chooses to tell us the truth, that we are very angry with ourselves indeed. When he does so, anger is swallowed up in admiration. The appearance of corpse after corse in the feast of death is entirely logical, and the main alibi, unshakeable except for Poirot, is of the first brilliance. It is no less likely than the run of such things in fiction, and is built not with many preliminary falsifications but almost in a single carefully premeditated flash of movement." He concluded, "Though less than secondary, the descriptive work is adequate and hits, as it were, the Nile on the head."