Smith, 34, was shot after exchanging words with the driver of a Hummer H2 that rear-ended his Mercedes G63 SUV, causing him to strike another vehicle, police said.
Smith was shot multiple times, and his wife, Racquel, also 34, was shot twice in the right leg, according to police. Smith was pronounced dead at the scene, while his wife was taken to a hospital.
Police said the 30-year-old driver of the Hummer was in custody and being interviewed, and that the handgun used in the shooting had been recovered.
The Saints also confirmed Smith's death, with a spokesman tweeting a statement:
Former Saints running back Pierre Thomas was on the scene shortly after the incident and reportedly had been out with Smith and his wife.
Smith was drafted by the Saints with the 18th overall pick in 2004 out of Ohio State. He spent all nine of his seasons with the Saints and last played in 2012. He was a Pro Bowler in 2006 and ranks fourth in Saints history with 67.5 career sacks. He had a career-high 13 during the Saints' 2009 Super Bowl season.
Saints head coach Sean Payton, along with some of Smith's former Saints teammates and fellow NFL players took to Twitter to express their grief: