The Last Ship begins with American helicopters flying into Egypt with Doctor Rachel Scott on board. She enters a quarantine zone and is met by a local doctor who is clearly upset that there aren’t more doctors with her. The local doctor shows her the latest victims of a new disease. They have spotted skin and the doctor says that once they get the spots they die in two days. Dr. Scott takes a blood sample from one of the infected, says she’s sorry, and leaves.
Cut to the USS Nathan James loading up for a mission. Commander Chandler meets Dr. Scott and her assistant, Quincy Tophet, who are setting up a lab in the ship’s helicopter bay. Dr. Scott tells the Commander that they’re studying birds and Chandler welcomes them aboard.
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Four months later, the Nathan James is in the arctic conducting the last in a series of weapon tests. Upon successful completion of the test, Commander Chandler sends out a team to retrieve Dr. Scott from the ice so that they can leave for home. Scott isn’t happy with the interruption. Once back on the ship, Scott argues with Chandler about it, but Chandler refuses to budge.
Dr. Scott gets on a satellite phone and demands to speak to the national security advisor to extend her mission. Meanwhile, Quincy is conducting tests on lab rats, injecting them with samples. Chandler contacts command and is ordered to remain in the arctic.
Dr. Scott goes back out on the ice and finds what she’s been looking for. Just then, several Russian helicopters appear and attack the area. The Nathan James and its crew engage the helicopters and eventually bring them down. They bring aboard a Russian. Chandler asks him what he wants and he says “the cure.”
Chandler takes Dr. Scott’s samples and demands and explanation for what’s going on. Scott explains that there was an outbreak of unknown origin in Cairo seven months ago. The CDC and WHO tried to create a vaccine, but nothing worked. Scott has been searching for the primordial strain in the arctic. She found it, but she needs to get back before she’ll know if it’s enough to create a vaccine. She reveals that she’s been in contact with her labs at home and that the virus has spread far faster than she expected. The virus has gone from phase 2 to phase 6, a global pandemic infecting 80 per cent of the world.
Chandler gets the president on a video call. She was speaker of the house, but the previous president and vice president both died from the virus. The president sends coordinates to a secure laboratory in Richmond. She says the Russians no longer have a functioning government, and that the world is sick, desperate, and dying.
Chandler and XO Slattery watch video footage of the chaos caused by the virus, realizing that their mission was only a cover for Scott. Chandler then fills in the rest of the crew.
We see a flashback of Chandler’s family as he stares at pictures from home. Chandler is informed that almost none of the crew has been able to make contact with home. Slattery found out that his son died, but his wife and daughters are alive and someplace safe for now.
The ship’s radar picks up a nuclear missile in the air. It overshoots the ship and lands somewhere near the English Channel. All of the ship’s electronics shut down. They try to reset the ship, but the fuse blows. Chandler holds the last fuse in with his own hand as they turn the power back on.
They pick up a ship on radar and decide to investigate. They find an Italian cruise ship. Chandler puts together a team and board the ship to find food and supplies. They find the crew and passengers dead from the virus and a fridge full of bodies. Chandler and Scott find someone still alive, but Scott says all they can do is give him morphine and takes a sample of blood. While moving down the stairs, Franklin trips and his mask falls off. Despite protests, he realizes that he’s been exposed to the virus and shoots himself rather than dying slowly.
Back on the ship, they give Franklin a funeral. Scott continues to work on her samples in the lab. After, she comes to the deck and tells Chandler that she’s found out why the virus spread so fast. It has an extra gene that was added by human intervention. The additional gene also makes the virus stable enough that she can make a vaccine for it using the primordial sample from the arctic.
A five day old message from the president arrives ordering the Nathan James to a different lab because the one in Richmond is not safe. They try reestablish communication but nothing goes through. An MPEG file arrives, a video message from Chandler’s wife. She says she’s at Chandler’s father’s cabin and that she and their children are safe, having left early and being in the cabin for months.
The ship arrives off the coast of Florida. Chandler asks Scott if she could make the vaccine on the ship. Slattery is preparing the crew to go inland, but Chandler stops him and tells him that’s no longer the plan. There’s no sign of a government, too much chaos on land, not enough power for a laboratory, and not enough biohazard suits to go around. Chandler plans to stay on the sea around the sea until Scott get the vaccine ready. Chandler orders the change in direction then gives a speech over the speaker informing the crew of his plan. He receives a salute from everyone on the bridge.
Quentin is on the SAT phone speaking in Russian and using code names “Arctic Fox” and “Seagull.” He tells them the ship won’t go inland and he doesn’t know what to do.