New Orleans placed Williams on injured reserve on Saturday due to a hamstring injury he sustained in the team's Week 2 win over the Panthers.
His trip to IR means he'll spend at least four weeks on the mend before possibly returning to the active roster.
The seventh-year RB came to New Orleans after a career season in Detroit, where he eclipsed 1,000 rushing yards for the first time and led the league with 17 rushing touchdowns to break the Lions' single-season franchise record.
He was expected to serve as the Saints' lead back in the early going while Alvin Kamara served his three-game suspension for violating the league's personal conduct policy, a punishment that stemmed from Kamara's arrest for battery in February 2022.
Williams struggled to find room in that role before the injury, though, rushing for just 74 yards on 27 carries and contributing another seven yards on two catches.
Third-round rookie Kendre Miller, making his debut after missing the first two weeks with a hamstring injury of his own, will fill in for Williams against the Packers on Sunday along with Tony Jones and the Saints' Swiss Army knife, Taysom Hill.
Then, Kamara is eligible to return on Monday in preparation for a Week 4 showdown against the Buccaneers.
The Saints have talent in their RB room to weather Williams' injury, just as they did Kamara's suspension, but the extended absence is still a tough blow.
It'll be another month at minimum before New Orleans gets its first look at its 2023 backfield in full.