Brown attended Miami Norland High School in Miami, Florida, where he was a two-sport athlete in both football and track. In football, Brown played running back, quarterback and wide receiver for the Vikings, and ran for 451 yards with 13 touchdowns, while he also threw for 1,247 yards and 11 scores in just five games. He was a two-time Class 6A all-state selection, and was also named North Athlete of the Year at 2005 Miami-Dade Gridiron Classic. In track & field, Brown was a two-time state qualifier in the 100-meter dash, and also ran the fourth leg on the Norland 4x100 m relay squad, helping them capture the state title at 41.50 seconds. He spent a prep year in 2006 at North Carolina Tech.
On September 19, 2010, against the Tennessee Titans, Brown made his regular season debut and had 128 yards on 3 returns (2 kickoffs, 1 punt), including an 89-yard touchdown from a reverse on the first play of the game. In the AFC Divisional Playoffs against the Baltimore Ravens, Brown caught a 58 yard pass on 3rd & 19 from quarterback Ben Roethlisberger to set up the game-winning touchdown. The following week in the AFC Championship against the New York Jets, at the two-minute warning, Brown caught a 14 yard pass on 3rd & 6, sealing the victory for Pittsburgh as they advanced to Super Bowl XLV.
On December 4, 2011, Brown returned his first punt return for a touchdown against the Bengals, and was also named AFC Special Teams Player of the Week. In 2011, Brown became the first player in NFL history to have more than 1,000 yards receiving and returning in the same year. For his efforts, Brown was selected as a punt returner for the Pro Bowl.
On July 28, 2012 Brown signed a 5-year, $42.5 million extension with the Steelers which included an $8.5 million signing bonus. On November 4, 2012, Brown was fined $10,000 by the NFL for unsportsmanlike conduct when he ran backwards for the final 20 yards of a punt return touchdown against the Washington Redskins.
On December 22, 2013, Brown broke Yancey Thigpen's team record of 1,398 receiving yards set in 1997. Brown also became only the second Steeler to amass at least 100 receptions in a season, joining former teammate Hines Ward. On December 29, he, along with Pierre Garçon of the Washington Redskins, tied Jimmy Smith as the only players to record at least five receptions in every single game of an NFL season in a win against the Browns, all while becoming the only receiver in NFL history to ever record five receptions for at least 50 yards in every single game of an NFL season. On December 27, 2013, Brown was selected for the Pro Bowl as a receiver and a punt returner. On January 3, 2014, Brown was named to the AP All-Pro team for the first time in his career.
On September 7, 2014, Brown returned a punt against the Cleveland Browns. During the return, Brown jumped, then kicked the Cleveland Browns' punter, Spencer Lanning, in the face. Brown later apologized, claiming it was an accident. On September 11, 2014, Brown was fined $8,200 for kicking the punter. On October 20, 2014, Brown threw his first career touchdown pass, a 3-yard pass to Steelers wide receiver Lance Moore. In 2014 Brown led the NFL in receptions, yardage, and was tied for second in touchdowns. Brown has extended his record of recording 5 catches for 50 yards to 32 consecutive regular season games. Browns' 2014 campaign saw him best his franchise-record yardage mark of 1,499 yards by gaining 1,698 yards on 129 catches, the highest total of catches in Steelers' history and good for second in NFL history, to go with a franchise-record 13 receiving touchdowns.