The news comes one day after quarterback Tajh Boyd said he would return to school for his senior season.
"It is tough to leave because this is my home, this is the place I wanted to play since I came out of the womb," Hopkins said in a statement. "But, I feel it is best for me and my family to take my talents to NFL at this time.
"I have to thank the Clemson alumni, the fans, the coaches and my teammates for all the support they have given me through the good times and the bad. No matter what, I will always be a Clemson Tiger."
Hopkins shattered the Clemson single-season record for receiving yards in 2012, finishing the season with 82 receptions for 1,405 yards and 18 touchdowns. He broke Sammy Watkins' record of 1,219 receiving yards in 2011.
He established ACC records for touchdown receptions in a season, consecutive games with at least one touchdown reception (10) and most games with a reception touchdown (12).
"Nuk was a big reason we won 11 games and reached a final No. 10 national ranking," coach Dabo Swinney said in a statement. "We have had many talks and he feels it is the best thing for he and his family. I fully support him in his decision."
"He will make an outstanding professional. He has the best hands and ability to catch the ball in traffic I have seen in a long time. He has done a lot for this program and we wish him much success at the next level. We all look forward to following his progress."
ESPN NFL draft analyst Mel Kiper rates Hopkins as the No. 3 junior receiver in the nation.
In all, Hopkins established Clemson career records for touchdown receptions (27), 100-yard receiving games (12), and total reception yards (3,020). He is second in total receptions with 206 in 39 career games. He also caught at least one pass in each of his last 36 games to tie Jerry Butler's record (1975-78).
Though losing Hopkins is big, the Tigers do return Watkins, the 2011 ACC Rookie of the Year who is eager to rebound after a roller-coaster 2012. And of course, they return Boyd -- one of the top quarterbacks in the nation.