Smith was a wide receiver for sixteen seasons in the National Football League (NFL), primarily with the Carolina Panthers, also playing for the Baltimore Ravens.

Smith attended University High School in Los Angeles, and was a letterman in football and track & field.

In track & field, he set a handful of school records, was named as an All-City selection as a high-hurdler, and also excelled in the triple jump and 300m hurdles.

During this time, Smith was teammates with future NFL wide receiver Chad Johnson, surprising fans of the small college team with their unexpected talents.

Smith took Taylor's advice to heart, and excelled in his academics, not missing a single day of classes while attending Santa Monica.

While at the University of Utah, Smith set a record for yards per catch with a 20.6 average, and was chosen to play for the conference's all-star team twice.

During the 2003 season, Smith played a critical role for the Panthers offense and helped lead them to their first NFC title in franchise history.

During the NFC divisional playoffs, Smith caught a 69-yard pass and ran it for a touchdown in the 2nd overtime period to defeat the St. Louis Rams 29–23.

Smith suffered a broken leg during the 2004 NFL season opener against the Green Bay Packers, and was out for the remainder of the year.

The Panthers then defeated the Chicago Bears in the divisional round, aided by Smith's franchise record 12 receptions for 218 yards and 2 touchdowns.

Smith, along with teammates Jake Delhomme, Julius Peppers, and Mike Wahle were invited to the 2006 Pro Bowl after the season.

Smith also shared the 2005 NFL Comeback Player of the Year Award with New England Patriots' linebacker Tedy Bruschi.

After suffering a hamstring injury and developing an ingrown toenail in training camp before the 2006 season, Smith returned to the field after missing two weeks of action.

Smith was double covered frequently but still managed to battle through that and injuries to finish the year with 83 catches for 1,186 yards and 8 touchdowns.

Smith made headlines during the 2008 training camp when he was involved in an altercation with teammate Ken Lucas on August 1, 2008.

Smith's low numbers were due to the total lack of team offense behind rookie quarterback Jimmy Clausen.

The Panthers finished last in most offensive categories and with a 2–14 record, which was the worst in the 2010 season, securing the 1st overall pick in the 2011 NFL draft.

Smith's dissatisfaction led to widespread rumors amongst the Panthers fan base that the star receiver wanted to be traded from the team for the 2011 season.

[19] Prior to signing with the Ravens, Smith stated that if he happens to meet his former team, the Panthers, again, to "put your goggles on cause there's going to be blood and guts everywhere.

[22] In Week 3 against the Cleveland Browns, Smith caught 5 passes for 101 yards, including a 32-yard reception that set up the game-winning field goal, as the Ravens won 23–21.

On the Ravens' second possession of the game, quarterback Joe Flacco threw a pass which was tipped by Owen Daniels and landed in the arms of Smith, who took the ball to the end zone for a 61-yard touchdown.

He picked up the ball and threw a pass to a covered Smith, who caught it in the back of the end zone, despite being held by cornerback Melvin White.

[27][28] In the divisional round of the playoffs, Smith caught three passes for 44 yards and a touchdown, as the Ravens lost and had their season ended by the eventual Super Bowl XLIX champion New England Patriots.

[32] In the Ravens' first win against the Pittsburgh Steelers in Week 4, he was forced to leave the game in third quarter due to a lower back injury he suffered after a hit from linebacker Lawrence Timmons.

[34] In a Week 8 game against the San Diego Chargers, Smith tore his achilles tendon, and it was announced he would be out for the rest of the 2015 season.

[50] In 2023, on his podcast, Cut to It, Smith referred to Jerry Jeudy of the Denver Broncos as "JAG", for "just a guy", an average player.

In response, Smith ranted about Jeudy on NFL Network, calling him "mentally unable to handle constructive criticism", and advised other teams not to trade for him.

[59] On June 14, 2017, it was reported by The Charlotte Observer that he secretly paid the full college tuition of Twitter personality and author Elexus Jionde.

"[60] In 2019, Smith played for the "Home" roster during the NBA All-Star Celebrity Game at the Bojangles' Coliseum in Charlotte, North Carolina.

[61] On July 9, 2019, the Panthers announced that Smith would be inducted into the team's Hall of Honor along with Jake Delhomme, Jordan Gross, and Wesley Walls.