The Bills sent the ninth overall pick along with their first- and fourth-round selections in 2015 to Cleveland in the trade -- one of five deals made during Thursday night's event.
"We went into this draft saying we were going to be bold, and we made a bold move," Bills CEO Russ Brandon said.
General manager Doug Whaley said the trade came at a "very high cost" for the Bills, who haven't made the playoffs since 1999 -- the NFL's longest postseason drought.
"We thought it was a calculated risk and a risk we were willing to take," Whaley said. "The high cost of not making the playoffs is something we weighed in and we thought this guy was going to get us to the playoffs."
The Browns were quite busy Thusday night as they were involved in three of the five trades, which matched last year's total for the first round.
Cleveland also acquired the No 8. overall pick from the Minnesota Vikings -- which they used to select cornerback Justin Gilbert -- and the No. 22 overall pick from the Philadelphia Eagles to draft quarterback Johnny Manziel.
In other moves, the New Orleans Saints traded up nine spots with the Arizona Cardinals to select receiver Brandin Cooks, and the Vikings used the Seattle Seahawks' final pick of the first round to select quarterback Teddy Bridgewater.
The Bills are being sold and the process could be completed as soon as this summer, but Brandon said the uncertain ownership future didn't weigh into the decision to give up the team's first-round pick next season.
"It's business as usual," Brandon said. "I'm not worried about anything relative to the sale of the franchise when it comes to the football operation."
With Watkins now in the fold, the Bills have a crowded depth chart at wide receiver. Stevie Johnson, the team's leading receiver from 2010 to 2012, could have a murky future with the Bills. He battled several injuries in 2013 and has an $8.5 million cap number this season.
"Stevie Johnson is on our team. He is under contract and that is another weapon in our arsenal," Whaley said.
The Bills drafted receiver Robert Woods in the second round last year and also sent a sixth-round pick last month to the Tampa Bay Buccaneers for receiver Mike Williams.
Watkins set a Clemson record with 240 receptions in his three seasons. He possesses great acceleration, competitiveness and big-play ability, as he led all receivers from AQ conferences with 1,044 yards after the catch last season, according to ESPN Stats & Information.
The 6-foot-1, 211-pound Watkins was one of college football's most exciting playmakers while with the Tigers, capping it with 101 receptions for 1,464 yards (14.5 yards per catch) and 12 touchdowns in 2013. He also averaged 9.2 yards per catch on screens last season, which is 3 yards better than the national average, according to ESPN Stats & Information.
He also has the ability to contribute on special teams, as he returned kickoffs and punts at Clemson.