New York Giants

Smith was drafted in the second round (51st overall) by the New York Giants in the 2007 NFL draft.^[5] He wore number 12. Smith only played in five games in the 2007 regular season (Weeks 1, 2, 15, 16, 17), recording eight catches for 63 yards and no touchdowns. However, after returning from a shoulder and hamstring injury, Smith turned in an outstanding postseason as he became a reliable third down receiver for quarterback Eli Manning. He made two big catches at the end of the first half in Dallas, which set up a game-tying touchdown and caught five passes in Super Bowl XLII, including four on third down. One of which was a 12-yard reception on a third and 11 with 45 seconds remaining in the fourth quarter.^[6] Smith and the Giants prevailed over the New England Patriots 17-14. In the 2008 regular season, Smith became one of Manning's favorite targets, and not just on 3rd down as Smith led the Giants in receptions over Amani Toomer and Plaxico Burress, who both started over Smith. Smith helped the Giants win the NFC East division.^[7]

In the 2009 season, with the Giants' loss of Burress and Toomer, Smith and Domenik Hixon were named the starting wideouts. Smith opened the season explosively, and by the end of week 4, Smith led the NFL in receptions (34), receiving yards (411), and touchdown receptions (4).

In Week 15, in a game against the Redskins, Smith broke the Giants franchise record for most receptions in a single season, also becoming the first Giants receiver in history to make 90 catches in one season.

Smith was selected as an alternate in the 2010 Pro Bowl. He later replaced Arizona Cardinals wide receiver Larry Fitzgerald on the 2010 Pro Bowl roster after Fitzgerald withdrew with an injury.

Philadelphia Eagles

On August 10, 2011, Smith agreed to a one-year, $2 million deal with the Philadelphia Eagles. He was placed on the active/physically unable to perform list on August 13. He was activated from the list on August 27.

He had eleven catches for 124 yards and a touchdown before he was placed on injured reserve on December 12 due to a bone bruise in his knee.^[8] He played in nine games for the Eagles, with one start against the Arizona Cardinals on November 13, in which he made five catches for 47 yards.

St. Louis Rams

The St. Louis Rams signed Smith on March 26, 2012.

Tampa Bay Buccaneers

On April 2, 2013, Smith signed with the Tampa Bay Buccaneers.^[9] Smith announced his retirement on May 29, 2013.^[10] Five years later, in his first year of eligibility, Smith was mistakenly announced as a modern-era nominee to the Pro Football Hall of Fame.^[11][12]