Smith was rear-ended while driving in New Orleans's Lower Garden District on Saturday night, causing him to hit a vehicle in front of him, police said. The driver of the vehicle that hit Smith, identified by police as Cardell Hayes, "exchanged words" with the former football player after the crash.
Hayes, 28, then drew a handgun and shot Smith several times, police said.
Hayes stayed at the scene, police said, and a handgun was recovered from the area. Hayes was arrested and charged with second-degree murder.
Smith's wife was also shot and transported to a local hospital. Police said her injuries were non-life-threatening.
Two acquaintances of Smith's witnessed the shooting, police said, but did not immediately identify them.
A judge set bond for Hayes at $1 million this afternoon, and the suspect did not enter a plea.
Hayes' attorney John Fuller said after the hearing that his client is not guilty, and implied that Hayes fired because he believed Smith was going for a gun of his own, The Associated Press reported.
New Orleans Police Superintendent Michael Harrison said police had no information leading them to believe that Smith and Hayes knew each other prior to the shooting.
Smith, who was 34, was drafted by the Saints in 2004 and spent all nine of his seasons with the team. He last played in 2012.
The Saints revealed today that Smith was voted into the Saints Hall of Fame last month. The news would have been made public in May.
Smith posted a photo the day of the shooting, writing "Having a blast" at New Orleans' French Quarter Fest.
A statement on behalf of Smith's family said they were "thankful for the outpouring of support and prayers." Saints head coach Sean Payton and former Saints player Deuce McAllister both called his death "senseless."
Other Saints players, including Nathan Stupar and Cameron Jordan, also offered their condolences.
The Saints' Vice President of Communications Greg Bensel called for the end of all "senseless killings" in New Orleans.
"I am shocked and saddened by the tragic loss of former New Orleans Saints player Will Smith," New Orleans Mayor Mitch Landrieu said. "My thoughts and prayers are with Will's family and those who loved him dearly.
"The senseless acts of violence have to stop," he continued. "Traffic accidents should not lead to someone losing their life."
NFL commissioner Roger Goodell called it "a tragic loss of life."
"Our thoughts are with Will's wife Racquel and their three children," Goodell said in a statement. "He will be missed by many teammates and friends."
"He was a role model," Paul Filletti, one of Smith's high school football coaches in Utica, New York, told ABC affiliate WSYR-TV. "He was the person that every kid in the city of Utica wants to be when they grow up."
The alleged gunman, Hayes, filed a lawsuit against the city of New Orleans and several New Orleans police officers in 2006 in connection with the deadly shooting of his father, Anthony Hayes.
Anthony Hayes was carrying a knife when he was shot by several New Orleans police officers in December 2005, according to the suit.
The New Orleans Advocate reported that it was settled in 2011 for an undisclosed amount of money.
The suit names William Ceravolo as one of the police officers, and according to the New Orleans Advocate, Ceravolo had dinner with Smith the night of the shooting.