Police were alerted to a crash involving three cars on the southbound side of the FDR Drive near Exit 11 for East 53rd Street.
One of the drivers, a 56-year-old man, was transported to New York-Presbyterian / Weill Cornell Medical Center, where he was pronounced dead.
The other two drivers were taken to a different hospital in stable conditions.
The accident shut down at least one lane of the FDR drive causing delays and bumper-to-bumper traffic that stretched past the Williamsburg Bridge at one point.
Police are still investigating what led up to the deadly crash.