More than one killer is aboard this train.

After a brutal year battling what should have been a terminal cancer diagnosis, mystery author Joe Penvale and his twin sister Meredith decide to celebrate this new beginning with a holiday on the famed Orient Express. Joining them in carriage 16 are a medically retired French police detective, a female British detective inspector, a travel blogger and her husband, two true crime podcasters who are seeking an interview with Joe, a widowed duchess, two little old ladies from Lower Slaughter in pursuit of a thief they know is aboard, and an obnoxious man in a green plaid suit. Joe and Meredith's elusive neighbor in 16G keeps to his cabin the first night after an early dinner—and the next morning his cabin is found soaked in blood, with no sign of his body anywhere.

Also aboard is a virulent new strain of coronavirus, which leaves an entire carriage under quarantine and the train itself prohibited from disembarking in Venice. Busy dealing with this crisis, the train's CEO cobbles together an investigative committee comprising seven passengers with backgrounds in law or law enforcement to look for clues. But when the steward guarding the crime scene is killed, and then another who'd been sent to fetch the traveler's passports, the accusations and in-fighting begin and Joe and Meredith begin snooping about on their own, risking their newly reclaimed lives in a desperate attempt to stop a killer before they strike again.