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.
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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.