Hopkins’ uncle on his mother’s side, Terry Smith, played wide receiver at Clemson and went undrafted before having a brief professional career with the Indianapolis Colts on their practice squad from 1995–1996. His time in the NFL was marred by knee injuries that ended his career. In 1997, Smith was shot and killed by Atlanta police after forcing his way into his estranged wife’s home and stabbing her. Police opened fire after Smith defied multiple orders. Close friends and former teammates said Smith was nonviolent but that his behavior had changed in the months leading up to his death. Smith played for Clemson from 1990-1993 and finished his collegiate career as the all-time leader in catches (162) and receiving yards (2,681). He was named the Tigers’ MVP for the 1993 season and was known for his game-winning touchdown in the 1993 Peach Bowl, defeating Kentucky with seconds left.

In July 2002, Greenlee had a boiling concoction of lye and bleach thrown on her by Savannah Grant, age 24. Greenlee had caught her boyfriend having an affair with Grant. The attack resulted in the skin rapidly peeling off her neck, face, and back. Her boyfriend picked her up, placed her in his vehicle, and dropped her off at a nearby gas station. The gas station attendant called 911, and Greenlee was rushed to a hospital and later flown to Augusta, Georgia, where she was placed in a medically induced coma for three weeks and had skin grafts applied to her face. Greenlee suffered burns over 17 percent of her body. Her attacker was charged with assault and battery with intent to kill and received a 20-year sentence. She has been incarcerated since 2003. Hopkins’ mother was left completely blind as a result of this attack.

Hopkins started his collegiate career with two receptions for 23 receiving yards in a 35–10 victory over North Texas on September 24. The next week, against Presbyterian, he scored his first collegiate receiving touchdown on a nine-yard reception from Tajh Boyd in the 58–21 victory. On November 13, in a road 16–13 loss to Florida State, he had eight receptions for 106 receiving yards. In the final game of the regular season, the Palmetto Bowl against rival South Carolina, he had seven receptions for 124 receiving yards and a receiving touchdown in the 29–7 loss. In the 2010 Meineke Car Care Bowl against South Florida, he had nine receptions for 105 receiving yards in the 31–26 loss to close out his freshman season. Hopkins was Clemson’s leading receiver with 52 receptions for 637 receiving yards and four receiving touchdowns. In addition, he played basketball after his freshman season.

Hopkins started the 2011 season with nine receptions for 108 receiving yards and a receiving touchdown in two games combined against Troy and Wofford. Against Auburn on September 17, Hopkins had seven receptions for 83 receiving yards and a receiving touchdown in the 38–24 victory. On October 22, against North Carolina, he had nine receptions for 157 receiving yards and a receiving touchdown in the 59–38 victory. Nearly a month later, against NC State, he had five receptions for 124 receiving yards in the 37–13 loss. In the ACC Championship against Virginia Tech, he had seven receptions for 92 receiving yards in the 38–10 victory. In the 2012 Orange Bowl, he had 10 receptions for 107 receiving yards and a receiving touchdown in the historic 70–33 loss to West Virginia. As a sophomore in 2011, he had 72 receptions for 978 receiving yards and five receiving touchdowns. He finished second on the team in the major receiving categories to Sammy Watkins.

Hopkins started the 2012 season off strong with 13 receptions for 119 receiving yards and a receiving touchdown in a 26–19 win over Auburn. One week later, against Ball State, he had six receptions for 105 receiving yards and three receiving touchdowns in a 52–27 victory. On September 29, against Boston College, had had 11 receptions for 197 receiving yards and a receiving touchdown in the 45–31 victory. In the following game, he had seven receptions for 173 receiving yards and two receiving touchdowns against Georgia Tech in a 47–31 victory. On November 3, in a game at Duke, he had four receptions for 128 receiving yards and three receiving touchdowns in the 56–20 victory. He closed out the regular season with one receiving touchdown in each of the last three games against Maryland, North Carolina State, and South Carolina. In the 2012 Chick-fil-A Bowl against LSU, he had 13 receptions for 191 receiving yards and two receiving touchdowns. In his junior season in 2012, Hopkins had one of the best receiving seasons in ACC history, with an ACC-best 1,405 yards on 82 catches and a school-record 18 touchdowns (second in the nation) earning First Team All-Conference honors. Hopkins, along with junior quarterback Tajh Boyd and wide receiver Sammy Watkins, combined to make one of the most prolific passing offenses in college football and broke many individual and career school records. Hopkins left Clemson with career record for receiving yards (3,020) and career touchdown receptions (27) with at least one score in each of the last 12 games. On January 10, 2013, Hopkins decided to forgo his senior season at Clemson and enter the NFL Draft.

Coming out of Clemson, Hopkins was considered a top prospect and received an invitation to the NFL combine. He completed nearly all of the combine drills, but was unable to finish the three-cone drill after suffering an apparent calf injury. On March 7, 2013, he chose to participate at Clemson’s pro day, along with teammates Malliciah Goodman, Jaron Brown, Brandon Ford, Jonathan Meeks, Dalton Freeman, Jonathan Willard, and six others. He performed the 40-yard dash, 20-yard dash, 10-yard dash, and positional drills for scouts and team representatives. Hopkins attended private workouts or visits with the Dallas Cowboys, Carolina Panthers, New England Patriots, and had two with the St. Louis Rams. At the conclusion of the pre-draft process, Hopkins was projected to be a first or second round pick by NFL draft experts and scouts. He was ranked as the third best wide receiver prospect by NFL.com draft analyst Josh Norris, the fourth best wide receiver by Sports Illustrated, and was ranked the fifth best wide receiver by NFLDraftScout.com and NFL analyst Mike Mayock.

The Houston Texans selected Hopkins in the first round with the 27th overall pick in the 2013 NFL Draft. He was the second wide receiver selected, behind Tavon Austin (St. Louis Rams, eighth overall). Hopkins was the second wide receiver in franchise history to be drafted in the first round, the first being Andre Johnson who was selected third overall in 2003. It was also just the second time in 10 years that the Texans selected an offensive player (the other selection was left tackle Duane Brown) in the first round. On July 24, 2013, Hopkins signed a four-year, $7.62 million contract with the team. The first three years of the contract were fully guaranteed.

Hopkins made his NFL debut in the season opener against the San Diego Chargers and made five receptions for 55 yards in the 31–28 victory. His first NFL reception came on a pass from Matt Schaub for no gain in the second quarter. On September 15, 2013, Hopkins caught a season-high seven passes for 117 receiving yards and scored his first career touchdown reception on a three-yard pass from quarterback Matt Schaub in the Texans’ 30–24 overtime victory against the Tennessee Titans. It was Hopkins’s first game with over one hundred receiving yards. In Week 7, he caught three passes for 76 yards and scored a touchdown on a 29-yard pass from Case Keenum during a 16–17 loss to Kansas City Chiefs. On December 2, 2013, Head coach Gary Kubiak was fired after the Houston Texans posted a 2–11 record. Hopkins finished the 2013 season with 52 receptions for 802 receiving yards and two touchdowns. His rookie season was marred by inconsistent quarterback play by Matt Schaub that led to Schaub’s benching after nine interceptions in five games. Hopkins was named to the NFL All-Rookie Team for the 2013 season.

Hopkins started in the season-opening 17–6 victory over the Washington Redskins and caught four passes for 89 yards and scored a new career-long 76-yard touchdown on a pass by quarterback Ryan Fitzpatrick. In Week 3, he had six receptions for 116-yards during a 30–14 victory over the New York Giants. In the game, Hopkins had a spectacular one-handed 53-yard catch that was negated by a illegial formation penalty. During a Week 7 matchup against the Pittsburgh Steelers, Hopkins made six receptions for 108 receiving yards in a 23–30 loss. On November 30, 2014, Hopkins caught a season-high nine passes for a season-high 238 receiving yards and two touchdowns as the Texans routed the Tennessee Titans 45–21 in Week 13. Hopkins was the Texans’ leading receiver in 2014, recording 76 receptions for 1,210 yards and six touchdowns in 16 games and 16 starts.

Hopkins also has three siblings, two sisters and one brother. His two older siblings, Kesha and Marcus, are from a previous relationship his mother had. His older sister, Kesha Smith, is a Southern Wesleyan University graduate. In 2014, she moved to Houston where she is a basketball trainer and a slot receiver for the Houston Wildcats of the Independent Women’s Football League. His younger sister, Shanterria Cobb, signed a letter of intent in the spring of 2016 to play basketball at Texas Southern University. She was a three-time all-region selection in basketball at D.W. Daniel High School. His older brother, Marcus Greenlee, was a standout football and basketball player in high school and briefly attended Georgia Military College.

Hopkins started in the Texans’ season-opener against the Kansas City Chiefs and caught nine passes for 98 yards and two touchdowns as the Texans lost 27–20. Two weeks later, he recorded his first 100-yard receiving game of the season, with eight receptions for 101 yards and a touchdown in a 19–9 victory over the Tampa Bay Buccaneers. Hopkins increased his production the following week, recording nine receptions for 157 yards in a 48–21 loss to the Atlanta Falcons. During Week 6 against the Jacksonville Jaguars he had 10 receptions for 142 yards and two touchdowns to earn his first career AFC Offensive Player of the Week award. During Week 13 against the Buffalo Bills, Hopkins broke the Texans’ franchise record for most touchdown receptions in a season, which was formerly held by Andre Johnson, with his tenth score. In the 2015 season, his usage increased to 192 targets, which ranked third among NFL wide receivers, trailing only Antonio Brown of the Pittsburgh Steelers and Julio Jones of the Atlanta Falcons.

On July 30, 2016, Hopkins did not report to training camp after he announced he was holding out for a new contract.

On September 15, 2016, Hopkins was fined $6,076 for an equipment violation regarding improper cleats on his shoes. The cleats were revealed to be Yeezy 350 Boosts cleats designed by Kanye West. In the 2016 season, Hopkins suffered through some small regression as the quarterback play of Brock Osweiler lacked positive consistency. The Texans finished atop the AFC South with a 9–7 record. They went on to lose in the Divisional Round of the 2016–17 NFL playoffs to the New England Patriots who went on to win the Super Bowl.

Hopkins had 78 receptions for 954 yards and four touchdowns in the 2016 season, all his lowest totals since his rookie season in 2013.

On August 31, 2017, the Houston Texans signed Hopkins to a five-year, $81 million contract extension with $49 million guaranteed and a signing bonus of $7.5 million.

During the season-opening 29–7 loss to the Jacksonville Jaguars, Hopkins caught the first NFL touchdown pass of quarterback and fellow Clemson Tiger Deshaun Watson’s career. He finished with seven receptions for 55 yards and a touchdown. During Week 8 against the Seattle Seahawks, Hopkins posted an impressive performance with eight receptions fo 224 receiving yards, which was highlighted by a 72-yard touchdown. However, his performance was overshadowed as the Texans lost on the road by a score of 38–41. On December 19, 2017, Hopkins was named to his second Pro Bowl. Hopkins did not play in Week 17 due to a calf injury.

On March 20, 2020, the Texans traded Hopkins and a fourth-round pick in the 2020 NFL Draft to the Arizona Cardinals for running back David Johnson, a 2020 second-round pick, and a 2021 fourth-round pick. Reception to the trade was highly critical, with many sportswriters calling it one of the worst of all time.

On September 8, 2020, Hopkins signed a two-year, $54.5 million contract extension with the Cardinals.

On September 13, 2020, Hopkins made his debut as a Cardinal against the San Francisco 49ers, recording a career-high 14 receptions for 151 yards in the 24–20 win. In Week 2 against the Washington Football Team, Hopkins caught eight passes for 68 yards and his first receiving touchdown as a Cardinal during the 30–15 win. In Week 3, he recorded ten receptions for 137 receiving yards in the 26–23 loss to the Detroit Lions. In Week 5 against the New York Jets, Hopkins recorded six catches for 131 yards, including a 37-yard touchdown reception, during the 30–10 win. In Week 7 against the Seattle Seahawks on Sunday Night Football, Hopkins recorded 10 catches for 103 yards and a touchdown during the 37–34 overtime win.