The 44-year-old driver had a medical issue that caused him to lose control of the SUV on Sixth Avenue at 41st Street just before 4 p.m., police said. The SUV hit an MTA commuter bus before coming to rest on its roof in the middle of the busy avenue.
The driver was rushed to Bellevue Hospital, where he was pronounced dead, police said.
No other injuries were immediately reported.
"It sounded like an explosion," said Josh Perez, 21, a security guard in the MetLIfe Building. "It was really, really loud."
Ajay Modi, 25, was walking near Bryant Park when he heard the crash, and he watched emergency responders pull the driver from the heavily damaged SUV.
"He wasn't moving," Modi said.
Police said the investigation was ongoing Friday evening.