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.