After a global pandemic kills or sickens possibly half of the world's population, the crew (consisting of 217 men and women) of a lone unaffected U.S. Navy guided missile destroyer, the fictional USS Nathan James (DDG-151), must try to find a cure and stop the virus in order to save humanity.

In July 2012, TNT ordered a pilot episode for a potential series based on the novel The Last Ship by William Brinkley.[10] Hank Steinberg and Steve Kane wrote the pilot script, and Jonathan Mostow directed the pilot.[11] It was filmed at a number of locations across San Diego including aboard the USS Halsey (DDG-97) and the USS Dewey (DDG-105), which stands in for the show's fictional USS Nathan James (DDG-151), and the USS Iowa museum ship

Cast:
Eric Dane as Commander Tom Chandler, commanding officer of the USS Nathan James (DDG-151)
Rhona Mitra as Dr. Rachel Scott, a paleomicrobiologist
Adam Baldwin as Commander Mike Slattery, executive officer of the Nathan James
Charles Parnell as Hugh Jeter, the ship's command master chief
Sam Spruell as Quincy Tophet, a paleomicrobiologist, and implied to be a Russian mole
Travis Van Winkle as Lieutenant Danny Green, leader of a SEAL team aboard the Nathan James
Marissa Neitling, as a Lieutenant Kara Foster, an officer working in the Combat Information Center
Christina Elmore as Lieutenant Alisha Granderson, co-steerer of the ship