Ishmael periodically finds himself restless, and so will join a ship as a sailor to refresh himself. Previously he has joined merchant ships, but this time he decides to join a whaling vessel, though his reasons are not entirely clear. Ishmael tries to find a place to stay, but the inn has no rooms so he is put up with Queequeg, a harpooner and a savage cannibal. Despite their differences in background and language (Queequeg can only speak a broken English), the two men become fast friends. Queequeg tells Ishmael that his god Yojo has told him that he must join whatever whaling vessel Ishmael ships with.

Ishmael finds a vessel, the Pequod, and signs up with them. Not long after, he meets a man named Elijah, who offers mysterious and unsettling commentary about any vessel that Ahab is a captain of. Despite these vague warnings, Ishmael still desires to join the Pequod and its crew. Queequeg has no difficulty in getting himself signed either, once they see his ability to handle a harpoon.

The journey begins on Christmas morning, when Ishmael sees mysterious figures boarding the ship before he does, and Elijah yet again enigmatically speaks of the journey to come. Aboard the ship, however, the figures are nowhere to be seen.

For the first few weeks of the voyage, Ahab does not leave his cabin, but as the weather warms, he comes on deck more and more to issue to orders and observe the crew. He has one leg made of ivory, and the ship is fitted to allow him to stand and move along it easily despite the handicap. One day, he stands before the crew and reveals his mad plan to hunt and kill Moby Dick. He offers the man who first spots the whale a gold doubloon. Starbuck becomes concerned that there captain would be so obsessed with a single whale, but he does nothing specific. As the voyage continues, and the men are able to hunt and kill other whales as normal, the first mate's fears subside a little, though it is clear that the men still think about their eventual goal.

They kill several whales, and meet several other ships as their journey continues. Ishmael also provides many factual details about the process of whaling the types of whales themselves. As they proceed closer to the Line, a massive feeding area where Ahab expects to find Moby Dick, the tension on the boat grows more intense. During one point, Pip the cabin-boy is flung off one of the whaling boats and left for a time until the Pequod picks him up. After, he becomes slightly mad. Queequeg grows ill at one point, and actually goes so far as to have a canoe coffin created for him for when he dies. When he does not die, however, the coffin is used to replace the lifeboat that subsequently becomes damaged.

The Pequod passes the Rachel, a ship whose captain is desperately searching for a lost boat which contains the captain's son. The missing boat was dragged off by Moby Dick after they darted the whale. Ahab, however, does not help, but instead continues on, knowing that the inevitable encounter is near.

The day before they find the whale, Ahab has a moment of understanding, and feeling for Starbuck and the family he has back in Nantucket, tells the mate he must not drop a boat to attack Moby Dick. The mate agrees, though tries again to convince Ahab he doesn't need to go after the whale either. The next day, the first day of fighting Moby Dick begins.

The Pequod drops their boats and goes after the great whale. Almost immediately, Moby Dick turns and destroys Ahab's boat, but no one is killed. They return to the Pequod and chase the whale until night fall. The next day they resume the chase and catch up with him yet again. They drop their boats and a long journey ensues, in which Moby Dick is darted many times. Eventually he tangles up the lines and destroys two boats before escaping again.

After more chasing, and another night of waiting, they set off to find the whale again. Eventually, Ahab realizes they have passed the whale, who is now slowed by all the harpoons. He stops only to see the whale behind him. He drops his boat and goes after him. The whale tips the boat and a sailor is thrown from the boat. The whale turns and runs right into the Pequod, breaking it open and causing it to sink. Ahab spears Moby Dick, but in trying to free the line, he is caught up in it and dragged under water to his death. Moby Dick leaves as the great boat sinks, all the men on board drowning with it.

Ishmael, the sailor thrown from Ahab's boat, survives when the coffin bursts up from the depths, allowing him to float upon it until rescued by the Rachel, still searching for their own lost boat.