Head coach Tom Coughlin called it "unlikely" that Barden will play again this season after suffering ligament damage and a fracture in his left ankle.
Barden walked through the locker room on crutches with a cast on his left foot on Monday. He injured his ankle on an incomplete pass in the back of the end zone in Sunday's game against the Dallas Cowboys near the end of the first half.
"He's got a significant ligament injury in the ankle and he does have a fracture down there as well," Coughlin said.
When asked if Barden can return this season, the coach replied, "That is unlikely right now."
Barden was elevated to the team's third wide receiver against Dallas with Smith out due to a pectoral injury.
Smith said he expects his partially torn pectoral injury to keep him out of this week's pivotal NFC East game against the Philadelphia Eagles and possibly longer.
Hakeem Nicks, Mario Manningham and rookie Duke Calhoun, who has yet to make an NFL regular-season catch, are the only healthy wide receivers remaining on the roster. Returner Darius Reynaud is listed as a receiver but he is nursing a hamstring injury. Tight ends Kevin Boss and Travis Beckum may factor more into the passing game now.
Boss, however, suffered a lower back sprain in the game against the Cowboys. He hopes to play Sunday night against Philadelphia.
The Giants recently waived Sinorice Moss from the injured reserve and the team says Moss is not eligible to return. Rookie receiver Victor Cruz was placed on injured reserve earlier this month with a hamstring injury. The Giants, who have wide receiver Samuel Giguere on the practice squad, could look to bring in a veteran receiver like Derek Hagan, who was with the Giants until he was released prior to the season.
Barden was just getting the first significant playing time of his young career. Drafted in the third round last year, the 6-foot-6 receiver is loaded with potential and had three catches for 34 yards before getting injured.
"Extremely [disappointing]," Coughlin said of losing Barden, who was improving. "He had gained some confidence, he was making some contributions. What Ramses needed to do was play. Put him in that situation, let him compete, let him play. Well, that was exactly what was going to happen and it is unfortunate that he will not be able to continue."
In other injury news, tackle-guard Kevin Boothe, who came off the physically unable to perform list last week, started at left guard Sunday and had to leave for a time with patella tendinitis. He returned and finished the game.