Smith underwent an MRI to his left knee on Tuesday. The Giants announced that he suffered an articular cartilage injury, the result of him being awkwardly tackled from behind in Monday's victory over the Vikings.
Smith's surgery has not been scheduled yet. He had just returned from a four-game layoff due to a partially torn pectoral muscle.
"Steve will not be able to play anymore," coach Tom Coughlin said. "I feel bad for Steve. He fights his way back and then [suffers] this injury. Our entire thoughts for the team are with Steve. First news was it may have been a hamstring or that type of injury."
Smith had 48 receptions for 529 yards and three touchdowns after making the Pro Bowl the previous season.
Meanwhile, No. 3 receiver Mario Manningham suffered a hip flexor injury against the Vikings on Monday.
"He does have an issue," Coughlin said of Manningham. "Hopefully he will make progress and hopefully he will be able to go [in practice] tomorrow."
Manningham said he suffered his hip flexor injury while trying to block on Brandon Jacobs' 73-yard run against the Vikings. While he said he didn't know how much he will practice this week, he vowed that he will play Sunday against the Eagles.
"I couldn't run and I couldn't dig [after suffering the injury on Monday night]," Manningham said. "I will be all right. Trust me. I'll be good to go Sunday at 1 o'clock.
"I have to work harder and watch more film and prepare myself harder knowing I will play [Smith's] position for the rest of the whole year."
Fellow wide receiver Hakeem Nicks said Smith will be missed.
"You know, [it's] very deflating but at the same time it is football, stuff happens," he said. "I pray a speedy recovery for him and I know he will be fine. His presence will definitely be missed in that slot on third-down situations and other situations as well."
Nicks played two games recently without Smith on the field. During that time, Nicks saw extra safety attention and had a total of 13 receptions for 147 yards and no touchdowns against Dallas and Philadelphia.
"Lately I have been seeing a lot of two-high, a lot of safety help over the top," Nicks said. "[Offensive coordinator Kevin] Gilbride has been doing a good job of moving me around a little bit. It will be fun."
The Giants are expected to eventually place Smith on injured reserve. This season, the Giants have had to put wide receivers Ramses Barden, Domenik Hixon, Sinorice Moss (who was later waived) and Victor Cruz on the season-ending IR.
While quarterback Eli Manning called Smith's injury unfortunate, he said the other receivers have to step up.
"We have Hakeem back and Mario, those guys are playing well," Manning said. "[Derek] Hagan has been here for a month and is playing well and Michael Clayton. We have numbers now, where we can put guys in different positions and they can go out there and play well."
Hagan, who has caught 13 passes since re-signing with the Giants four games ago, said it's all hands on deck for the injury-ravaged wide receiver corps.
"It's almost like every year there is one position which is always hurt on any team," said Hagan, who was cut at the end of training camp. "It was the DBs last year. It's unfortunate, but injuries happen in this game and you have to have guys who can come in and play right away. Obviously, the team brought me back for a reason, to help this team win and I got to do what I got to do to get this victory."
Dr. Russell Warren examined Smith at the Hospital for Special Surgery on Tuesday and diagnosed the injury to the fourth-year player's articular cartilage.
Dr. Michael Kelly, the chairman of department of orthopedic surgery at Hackensack University Medical Center, said the recovery period from surgery involving articular cartilage can be lengthy because the cartilage has no ability to regenerate itself. Kelly said the articulate cartilage helps cushion the bone.
"If articular cartilage surgery is performed, depending on the surgical procedure itself, the recovery involves limited weight bearing, so an extensive period on crutches, and then limited impact activity, such as running for many months," Kelly said in a telephone interview with The Associated Press. "It depends on what they do, the size and location. It all influences the recovery significantly. No matter how you do it, it takes awhile."
Kelly said Smith has a chance to be ready for training camp.
In other injury news, linebacker Clint Sintim made his trip to injured reserve Wednesday with a torn anterior cruciate ligament. The Giants signed defensive end Alex Hall to the roster, added linebacker Kenny Ingram to the practice squad and waived defensive tackle Joe Joseph.