In October 1991, the commercial fishing boat Andrea Gail returns to port in Gloucester, Massachusetts, with a poor catch. Desperate for money, Captain Billy Tyne convinces the Andrea Gail crew to join him for one more late-season fishing expedition. The crew heads out past their usual fishing grounds on the Grand Banks of Newfoundland, leaving a developing tropical storm behind them. Initially unsuccessful, they head to the Flemish Cap, where their luck greatly improves. At the height of their fishing, the ice machine breaks down; the only way to sell their catch before it spoils is to hurry back to shore. After debating whether to sail through the building storm or to wait it out, the crew decides to risk the storm. However, between Andrea Gail and Gloucester is a confluence of two powerful weather fronts and a hurricane, which the Andrea Gail crew underestimates.
After repeated warnings from other ships, Andrea Gail loses her antenna, forcing Captain Linda Greenlaw of sister ship Hannah Boden to call in a Mayday. A New York Air National Guard HH-60 Pave Hawk rescue helicopter responds, but after failing to perform a midair refueling with an HC-130 Hercules, the helicopter crew ditch their aircraft. All but one of the Air National Guard crew members are rescued by a Coast Guard vessel, the USCGC Tamaroa.
After Andrea Gail endures various problems, the crew struggles to sail through pounding waves and shrieking winds, while friends and family worry and wait for a ship that never comes home. The vessel encounters an enormous rogue wave. They attempt to drive the boat over the wave but it crests before it can get to the top and is overturned; Billy elects to go down with his ship, the rest of the crew are trapped inside and only one, rookie fisherman Bobby Shatford, manages to get out. He surfaces and watches as Andrea Gail rights herself before sinking stern-first into the Atlantic. As Bobby silently says his goodbyes to his loved ones, the rapidly rising swell carries him away.
There are no survivors; Linda reads the eulogy at the memorial. Later, as she heads out to sea again, she remembers Billy soliloquizing about what it means to be a ship captain.