A woman and two children, aged two and four, are in critical condition and a 13-year-old girl and a 37-year-old woman are stable after the shooting in the Lower 9th Ward.
The neighbourhood has struggled with crime since being ravaged by Hurricane Katrina in 2005.
Police said the victims were all were in front of a house when a dark car occupied by men drove up, opened fire and sped off.
The dead man appeared to be in his late 20s, a police spokesman said.
The Lower Ninth, a predominantly black neighbourhood less than five miles from the bustling tourist district of the French Quarter, was overwhelmed by Hurricane Katrina's floods in 2005.
In a separate incident, a 20-year-old man shot and badly injured a friend in a hotel at the edge of the Quarter, then killed himself after a three-hour stand-off with police.