In 1983, when Burleson was an infant, his father signed with the Los Angeles Express of the United States Football League (USFL), moving the family back to the United States. However, Burleson remains proud of his Canadian heritage, sporting a maple leaf tattoo and expressing interest in playing for Canada in a World Cup of football to the media. After an injury ended Alvin Burleson’s playing career, he moved the family to his hometown of Seattle, Washington, U.S., where he worked for Associated Grocers. Nate Burleson attended Rainier View Elementary School in Seattle. He attended Lindbergh High School in the suburb of Renton as a freshman, and then transferred to O’Dea High School in Seattle, where he graduated. As a senior, he was named Seattle Times City Athlete of the Year.

Burleson was also on the school’s track and field team, competing as a sprinter and hurdler. He won the state title in the 300-meter hurdles with a time of 38.70 seconds in 1999, and finished eighth in 110-meter hurdles as junior.

Burleson hoped to attend the University of Washington, his father’s alma mater, but was not offered a football scholarship. Instead he accepted a scholarship offer from the University of Nevada, Reno and played for the Nevada Wolf Pack. In the 2002 season he made 138 receptions, the second highest in NCAA history. His senior year, he led the NCAA in both receiving yards and in receptions per game. During his time at Nevada he made a total of 248 receptions for a total of 3,293 yards and 22 touchdowns. He was named first-team All-America by the American Football Coaches Association, All-WAC by the Western Athletic Conference (WAC), and team MVP, and was named second-team All-America by The Sporting News and CNN/SI. He currently holds the WAC and Nevada all-time records for single game receptions with 19 catches. He graduated with a degree in human development and family studies.

On March 24, 2006, Burleson signed a seven-year $49 million offer sheet to play with his hometown Seattle Seahawks. In retribution for the Vikings signing an offer sheet with former Seahawks guard Steve Hutchinson, the Seahawks put clauses in Burleson’s offer sheet which made it virtually impossible for Minnesota to match (similar to what the Vikings did with Hutchinson). The offer sheet stated that the entire $49 million would be guaranteed if Burleson played five games, in one season, in the state of Minnesota, or if his average per year exceeded the average of all running backs on the team combined. The Vikings played eight home games a year in Minneapolis, and at the time of the offer sheet, the team spent far less than $7 million per year for its entire running back corps. On the other hand, Seattle was spending over $7 million a year on just one of its running backs (Shaun Alexander). The Vikings had seven days to match the offer sheet but declined to do so. Minnesota received Seattle’s third-round pick in the 2006 NFL Draft; Seattle, however, received no compensation for the departure of Hutchinson. On September 7, 2008, Burleson tore a ligament in his knee in Seattle’s season opener against the Bills. He was put on injured reserve for the remainder of the season.

During the early hours of the NFL free agency period on March 5, 2010, Burleson agreed to a five-year $25 million contract with the Detroit Lions. Burleson reunited with his former offensive coordinator, Scott Linehan, with whom he had his best season of his career in 2004, when he caught 68 passes for 1,006 yards and nine touchdowns while playing for the Vikings. In 2011, Burleson was named recipient of the Detroit Lions-Detroit Sports Broadcasters Association/Pro Football Writers Association’s Media-Friendly “Good Guy Award” for his interactions with the media in. On September 24, 2013, Burleson fractured his forearm in two places in an early morning, single-car accident. It was reported that Burleson was attempting to save a pizza from falling off a seat in his car and lost control of his vehicle. He was cut from the Lions on February 13, 2014.

Burleson attended a Broadcast Boot Camp put on by the NFL in 2012. After his playing career ended in 2014, he began working as an analyst for the NFL Network. In 2015, Burleson was also a member of the Detroit Lions preseason broadcast team as a color commentator for the Detroit Lions Television Network. In 2016, Good Morning Football debuted on NFL Network with Burleson, Kay Adams, Kyle Brandt, and Peter Schrager as co-hosts. Burleson joined the NFL on CBS team as a studio analyst for The NFL Today for the 2017 season, while still serving as co-host of Good Morning Football.

On April 6, 2014, Burleson signed a one-year deal with the Cleveland Browns, but was cut on August 30.