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.
Smith's family released a statement Sunday morning.
"On behalf of the Smith family, we are thankful for the outpouring of support and prayers," the family said. "We ask that you continue to respect the family's privacy as they grieve the loss of a devoted husband, father and friend."
Police said the driver of the Hummer, Cardell Hayes, 28, has been charged with second-degree murder and that the handgun used in the shooting had been recovered.
The Saints also confirmed Smith's death, with Saints owners Tom and Gayle Benson and general manager Mickey Loomis releasing statements.
"Our thoughts and prayers are with Will and his wife Racquel, but more importantly with their children, William, Wynter and Lisa who are suffering and just starting to realize and deal with an unimaginable loss," Tom and Gayle Benson said. "We are devastated and saddened by Will's tragic and preventable death due to a senseless act that will leave a lasting scar on our community forever."
Said Loomis: "Will came to New Orleans 12 years ago and quickly developed both on the field as a player and off the field as a leader to become one of the cornerstones of a team that would go on to win a Super Bowl. In our community he was an important contributor to numerous charitable causes to benefit those in need. Will's contributions to both our franchise and our community as a whole will always be remembered."
NFL commissioner Roger Goodell called the killing "such a tragic loss of life" in a statement and said the league's thoughts were with Smith's wife and children.
New Orleans Mayor Mitch Landrieu said in a statement that he was "shocked and saddened" by Smith's death.
"The senseless acts of violence have to stop," Landrieu said. "Traffic accidents should not lead to someone losing their life."
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.
"I am shocked and deeply saddened by the tragic loss of Will Smith, my close friend and client," agent Joel Segal said in a statement. "Will was loyal, tough, smart, caring and funny all at once. He was an amazing man whose true joy came from his special family. From my first meeting with Will at Ohio State to our business meetings, fun dinners and spirited and intelligent debates, he always treated me like family.
"My heart goes out to Will's wife, Racquel, his children and entire family for this unimaginable loss. I love you, William. You will be missed and never ever forgotten."
Smith was elected by a panel to the Saints Hall of Fame last month in his first year of eligibility. The formal announcement had not yet been made.
"Hearing of Will Smith's murder this morning is absolutely devastating. He was a good man and a former team captain. The NFL was lucky to have him, and I always enjoyed playing against him," Whitworth said. "This is yet another example of the senseless violence we are experiencing daily as a country. My family and I are praying his wife recovers fully from her injuries, and will continue to keep his children, family members and former teammates in our prayers."
Saints coach Sean Payton, along with some of Smith's former Saints teammates and athletes throughout sports, also expressed their grief on Twitter: