He played college football for the Hofstra Pride, and was selected by the New Orleans Saints in the seventh round of the 2006 NFL draft.

He helped the Saints achieve victory in Super Bowl XLIV with seven receptions for 83 yards against the Indianapolis Colts.

Despite favorable statistics compared to other Pro Bowl or All-Pro players in the same position like Brandon Marshall and Reggie Wayne, Colston was never selected for either in his career.

[1] Colston attended Susquehanna Township High School, in Harrisburg, Pennsylvania, and was a letterman in football and track.

He qualified for the 2001 Pennsylvania Interscholastic Athletic Association (PIAA) Outdoor T&F Championships in the javelin, recording a top-throw of 57.03 meters.

Colston redshirted the 2004 season due to a shoulder injury, but in 2005 was named to the All-Atlantic 10 First-team after making a career-high 70 receptions for 976 yards (13.9 avg.)

In four seasons at Hofstra, Colston appeared in 40 games (37 starts) and recorded 182 catches for a school-record 2,834 yards and 18 touchdowns.

He was tipped in many prospect profiles to become a tight end, because of his size and catching ability, but was also predicted to go undrafted.

[13] Throughout training camp, Colston competed to be the third wide receiver on the depth chart against Devery Henderson, Lance Moore, and Terrance Copper.

[15] In Week 3, in a game on the road against the Carolina Panthers, Colston recorded an 86-yard receiving touchdown in the 21–18 loss.

[17] On October 29, Colston caught six passes for 163 receiving yards and had a season-high two touchdown receptions during a 35–22 loss against the Baltimore Ravens in Week 8.

[22] In Week 10, Colston recorded 10 catches for a season-high 169 receiving yards during a 38–31 loss at the Pittsburgh Steelers.

[24] Colston finished his rookie season with 70 receptions, 1,038 receiving yards, and eight touchdowns in 14 games and 12 starts.

[26] The Saints defeated the Philadelphia Eagles in the Divisional Round and made it to the NFC Championship Game with the Chicago Bears.

[29] He tied for second in voting for Offensive Rookie of the Year, behind Tennessee Titans' quarterback Vince Young, and with Jacksonville Jaguars' running back Maurice Jones-Drew.

[31] Against the San Francisco 49ers on October 28, 2007, Colston caught a career-high three touchdown passes from Drew Brees and guided the Saints to a 31–10 victory in Week 8.

[39] In 2008, Colston suffered a broken thumb after a hit by Ronde Barber on a quick slant pass in the Saints' Week 1 victory over the Tampa Bay Buccaneers.

[48] In the Divisional Round against the Arizona Cardinals, Colston had six receptions for 83 receiving yards and a touchdown in the 45–14 victory.

[52] The Saints returned to the playoffs but failed to repeat as Super Bowl Champions, falling in the Wild Card Round to Seattle Seahawks in the Beast Quake game.

[58] Colston, along with Jimmy Graham, gave the Saints their first duo with at least 1,000 receiving yards since Willie Jackson and Joe Horn in 2001.

On the ensuing drive, Brees spiked the ball to stop the clock, then found Colston near the sideline.

Part of his statistical decline was due to the emergence of Brandin Cooks and Willie Snead as receiving options for Brees to go along with shoulder and chest injuries causing him to miss three games.

Only Philip Rivers and Antonio Gates, a tight end, had more receiving touchdowns in that time span as a duo.

[90] Colston has pursued an executive MBA program at George Washington University,[91] and he has made a series of investments in startup companies operating in the health and sports sectors.

[95] On October 27, 2019, Colston was inducted into The New Orleans Saints Hall of Fame alongside Reggie Bush.