Wayne is the youngest of three sons. His father, Ralph, is a former linebacker for Grambling State. A New Orleans Saints fan in his youth, he was more interested in baseball growing up but chose football by the time he attended John Ehret High School.
Wayne attended the University of Miami, where he was a four-year starter for the Miami Hurricanes football team. He set a school record of 173 career catches (including 36 consecutive games with a reception) and is one of only five wide receivers in school history to post 20 or more touchdowns in his career, along with Michael Irvin, Lamar Thomas, Leonard Hankerson, and Andre Johnson. His 48 receptions during the 1997 season set a school record for freshmen, which still stands today. Wayne also ran track and field at the University of Miami, where he recorded a personal best of 21.87 seconds in the 200 meters. Wayne graduated with a degree in liberal arts; his roommate was Baltimore Ravens safety Ed Reed.
Wayne was inducted into the University of Miami Sports Hall of Fame at their 43rd Annual Induction Banquet held on March 24, 2011.
Wayne was selected by the Indianapolis Colts with the 30th selection in the 2001 NFL Draft, and was taken to eventually complement the Colts' other star receiver, Marvin Harrison.
In Wayne's first year, he caught 27 passes for 345 yards with no touchdowns. He only made nine starts and missed three games altogether due to a high ankle sprain. His yards doubled the next year as he caught 49 passes for 716 yards and four touchdowns.
Wayne broke into the starting lineup in the 2003 season, and he caught 68 balls for 838 yards and seven touchdowns. The next season, Wayne caught 77 passes for 1,210 yards and 12 touchdowns during a season in which Colts quarterback Peyton Manning set a then-record by throwing for 49 touchdowns. During the playoffs, Wayne was named the "Wild Card Weekend Offensive Player of the Week" after the Colts beat the Broncos. In 2005 Wayne continued to increase his yearly reception total with 83.
In 2006, Wayne signed a 6-year, $39.5 million contract. He went on to catch 86 balls for a then career high 1,310 yards and 9 touchdowns. As a result, Wayne was selected to his first Pro Bowl. Wayne helped the Colts defeat the Chicago Bears in Super Bowl XLI with a 53-yard touchdown reception in the first quarter.
In 2007, Wayne responded to a rash of injuries on the team, including Harrison and tight end Dallas Clark, and set a then career high in receptions (104), and a career-high in yards (1510). He led the league in receiving yards and was selected to go to the Pro Bowl for the second consecutive year.
In 2008, Wayne once again posted another Pro Bowl season with 82 catches for 1145 yards and six touchdowns, including a 65-yard score in the opening drive against the Pittsburgh Steelers.
In 2009, Wayne caught the winning touchdown pass against the New England Patriots in what is now known as the "4th and 2" game. Wayne was also selected as a starter for the Pro Bowl, but couldn't play due to the Colts playing in the Super Bowl. In Super Bowl XLIV, Wayne had 5 catches for 46 yards, but the Colts lost to the New Orleans Saints 31-17.
In 2010, Wayne was second in the NFL receptions with 111 (a career-high), and third in receiving yards with 1,355. During a season where the Colts heavily relied on Peyton Manning to win games, Wayne again cemented himself as one of the top receivers in the NFL. Wayne was also selected as a starter the Pro Bowl.
Wayne's numbers were lower than usual in 2011 without Peyton Manning starting at quarterback. Despite the lower numbers, Wayne led team in receptions (75) and receiving yards (960). He had four touchdown receptions as well. On September 25, 2011, Wayne recorded his 800th catch against the Pittsburgh Steelers.
On March 13, 2012, the Colts re-signed Wayne to a three-year contract.
Before the 2012 Week 5 matchup with the Green Bay Packers, the news of head coach Chuck Pagano's leukemia surfaced. Wayne's history with Pagano goes back to his college years, where Pagano was the Hurricanes' defensive backs coach, and Pagano's hiring as the Colts' head coach was a large factor in Wayne's decision to re-sign with Indianapolis. In Week 5, Wayne caught 13 passes for a career-high 212 receiving yards and a touchdown from rookie quarterback Andrew Luck. The touchdown came with 35 seconds left and proved to be the winning score. The Colts won 30-27, and Wayne earned the AFC Offensive Player of the Week award due to his performance, the first of his career.
In Week 12 against Buffalo Bills, Wayne broke Cris Carter's record of consecutive games with 3 or more receptions with 59 games. He also passed former Washington Redskins receiver Art Monk for 12th on the NFL's all-time receptions list during the first half. Monk finished his career with 940 catches.
During a 2012-13 wild-card playoff game against the Baltimore Ravens, Wayne had 114 yards on nine receptions and moved into second in career playoff catches with 92 — only 59 behind leader Jerry Rice. However, the Colts lost the game 24-9.
Wayne was selected as the wide receiver for USA Football’s 2012 All-Fundamentals Team, which honors 26 NFL players each year for executing the fundamentals of their position. In a 9–19 loss to the San Diego Chargers on October 14, 2013, Wayne reached 1,000 career receptions, becoming only the ninth receiver to do so. However, a week later, in an October 20 game against the Denver Broncos, Wayne tore his ACL; it was announced the next day that he would miss the remainder of the 2013 season. The injury also ended his consecutive games played streak at 189, the third-longest for a wide receiver in NFL history.
On October 19, 2014, Wayne became the ninth receiver in NFL history to record 14,000 receiving yards. He suffered an elbow injury in the game and missed the following week's matchup against the Pittsburgh Steelers. Near the conclusion of the Colts' 2014 season, it was announced that Wayne had played with a torn triceps since Week 6, which would require an offseason surgery to repair.
On March 6, 2015, the Colts announced that they would not re-sign Wayne, which made him a free agent on March 10.
On August 24, 2015, Wayne signed a one-year contract with the New England Patriots worth up to $3 million. On September 5, 2015, Wayne requested and was granted his release from the Patriots.
On January 15, 2016, after not playing the entire 2015 season, Wayne announced his retirement from professional football, saying, "It was fun, but it's time. It's just time. Whenever you can admit that you're done, you know you're done." He finished his NFL career seventh all-time in career receptions, eighth all-time in receiving yards and 23rd in career touchdown receptions.