Lewis was born in Los Alamitos, California. He graduated from Long Beach Polytechnic High School in Long Beach, California, where he played high school football for the Long Beach Poly Jackrabbits. In 2001, he competed in a nationally televised game against De La Salle of Concord, California. As a senior, Lewis was named as a Parade magazine high school All-American and was considered a top prospect by all major recruiting services.

Lewis attended UCLA, and played for the UCLA Bruins football team from 2002 to 2005. In 49 games with the Bruins, he started 32 times. He ranks ninth on the school’s overall career-record receiving list and first among tight ends with 126 receptions, holding the UCLA tight end all-time records with 1,571 yards receiving and 21 touchdowns. As a senior in 2005, Lewis was a first-team All-Pacific-10 selection, a consensus first-team All-American, and won the John Mackey Award, given annually to the top tight end in college football.

Lewis was selected by the Jacksonville Jaguars with the 28th overall pick in the first round of the 2006 NFL Draft. He played college football with running back Maurice Jones-Drew at UCLA who was also selected on the first day by the Jaguars. In July 2006, Lewis signed a five-year, $7.5 million contract that included $4.9 million guaranteed.

Lewis made his NFL debut in Week 1 of the 2006 season against the Pittsburgh Steelers in a 9–0 victory. He scored his first professional touchdown on a one-yard reception from David Garrard in Week 12 against the Buffalo Bills. He finished his rookie season with three starts in 15 appearances. He totaled 13 receptions for 126 receiving yards and one receiving touchdown. His role expanded in the 2007 season with 37 receptions for 391 receiving yards and two receiving touchdowns. He started all 16 games in his second year. In 2008, Lewis started all 16 games once again and recorded 41 receptions for 489 receiving yards and two receiving touchdowns, which came in consecutive games in Week 5 and Week 6. In the 2009 season, he started all 16 games and recorded 32 receptions for 518 receiving yards and two receiving touchdowns.

In the 2010 season, Lewis matched the Jaguars single-season touchdown receptions record with a total of 10 and was selected to his first Pro Bowl. He had previously been named as an alternate for the 2009 Pro Bowl. He started all 16 games and had three games with multiple receiving touchdowns.

Due in part to the 2011 NFL lockout, the Jaguars placed the franchise tag on Lewis on February 24, 2011. On August 5, 2011 after a short training camp hold out, Lewis signed a five-year contract reportedly worth about $35 million ($17 million guaranteed). In the 2011 season, he started in and appeared in 15 games and totaled 39 receptions for 460 receiving yards. For the first time in his professional career, he did not have a touchdown In the final game of the 2012 regular season against the Tennessee Titans, Lewis had seven receptions for 103 receiving yards for his first game going over the 100-yard mark. He totaled 52 receptions for 540 receiving yards and four receiving touchdowns on the season. In the 2013 season, he totaled 25 receptions for 359 receiving yards and four receiving touchdowns in 11 games. The four receiving touchdowns all came in four consecutive games from Week 13 to Week 16. In the 2014 season, he totaled 18 receptions for 206 receiving yards and two receiving touchdowns. Lewis continued his constant production in the 2015 season with 16 receptions for 226 receiving yards in 16 games, all starts.

On March 9, 2016, Lewis re-signed a three-year, $12 million contract to remain with the Jaguars. He was placed on injured reserve on November 21, 2016 after suffering a calf injury in Week 11 against the Detroit Lions. He totaled 20 receptions for 169 receiving yards and one receiving touchdown in ten starting appearances. In Week 3 of the 2017 season, he recorded four receptions for 62 receiving yards and a career-high three receiving touchdowns in a 44–7 victory over the Baltimore Ravens. He finished with 24 receptions for 318 receiving yards and five receiving touchdowns in 16 starts. In the AFC Championship loss to the New England Patriots, Lewis recorded his first postseason touchdown on a four-yard reception from Blake Bortles.

On March 20, 2018, Lewis was released by the Jaguars after 12 seasons with the team.

On May 24, 2018, the Green Bay Packers signed Lewis to a one-year, $2.1 million contract that included a $500,000 signing bonus.

Lewis caught his first pass as a Packer on November 4, 2018 during a Week 9 loss to the New England Patriots. He finished the 2018 season with three catches for 39 yards.

On March 18, 2019, Lewis re-signed with the Packers on a one-year, $2.1 million dollar contract.

Lewis caught his first touchdown as a Packer, a one-yard reception from Aaron Rodgers, on December 1, 2019 during a Week 13 victory over the New York Giants. He finished the 2019 season with 15 receptions for 156 receiving yards and one receiving touchdown.

On March 24, 2020, Lewis re-signed with the Packers on a one-year contract.