Starting defensive end Marcus Davenport will have season-ending foot surgery after being injured in the second half against the 49ers. Sheldon Rankins, another key member of the defensive line rotation, also has been lost for the remainder of the season following an ankle injury in the 48-46 defeat.
Both players have been placed on injured reserve.
Davenport, a first-round draft pick in 2018, also had foot surgery following his rookie season. He returned to start 13 games this season with six sacks, 16 quarterback hits and three forced fumbles.
The 6-foot-6, 265-pounder hit a bit of a lull in the middle of the season, but he came up huge in Weeks 12-13 when he totaled three sacks and two forced fumbles and affected a missed field goal by the Carolina Panthers in the final minutes by leaping over the line.
Davenport will be greatly missed by a defense that already was relatively thin at defensive end.
The Saints will likely count more on third-year backup defensive end Trey Hendrickson, who also was dinged up in Sunday's game.
Spence, 25, had a terrific rookie year with the Tampa Bay Buccaneers in 2016 with 5.5 sacks and three forced fumbles after being drafted in the second round. His production has tailed off since, however, and he was released at the end of this preseason. The 6-foot-2, 252-pounder later signed with the Washington Redskins and played seven games with them, recording one sack.
This is now the second straight season-ending injury for Rankins, who was a first-round draft pick in 2016. He tore his Achilles during the Saints' playoff opener in January after having a breakout season in 2018.
Rankins returned from the torn Achilles in Week 4 and was recently voted by teammates as this year's Ed Block Courage Award winner for overcoming adversity. He had 10 tackles and two sacks in 10 games, while also being a part of New Orleans' stellar run defense.
The Saints are deeper at defensive tackle to help compensate for Rankins' loss. Starter David Onyemata and backups Mario Edwards Jr. and Shy Tuttle could all play greater roles along with starting nose tackle Malcom Brown.
Before Sunday, the Saints' defense had been a strength for much of this season, helping them win games by scores of 12-10 and 13-6 while Drew Brees was out with a thumb injury. The Saints rank 13th in the NFL with 338.3 yards allowed per game, and are tied for fourth with 43 sacks and fifth with 94.2 rushing yards allowed per game.