Flames broke out inside the kitchen of Barbetta Restaurant at 321 West 46th Street, when it was peak capacity.
The grease fire spread to the vents in the walls and ceilings, forcing diners to leave.
It took more than 100 firefighters over a hour to extinguish the blaze.
The damage to the kitchen will force the restaurant to stay closed for at least a few days.
The elegantly decorated eatery bills itself as the oldest Italian restaurant in New York City.
The restaurant's famous diners include former President Bill Clinton and former Secretary of State Hillary Clinton.
Barbetta was founded in 1906 by owner Laura Maioglio's father, Sebastiano Maioglio.