Coming out of college, Dupree was projected to be a first round draft pick by the majority of NFL analysts. He received an invitation to the NFL combine and completed the majority of combine drills. Dupree was unable to perform the bench due to a pectoral injury and opted to not run the short shuttle and three-cone drill after suffering a groin injury. On March 12, 2015, he participated at Kentucky's pro day and performed very well in positional drills, the short shuttle, and three cone drills for scouts and teams representatives from 26 NFL teams. Minnesota Vikings' head coach Mike Zimmer, Cincinnati Bengals' head coach Marvin Lewis, and Pittsburgh Steelers' head coach Mike Tomlin attended to scout Dupree, Za'Darius Smith, Braylon Heard, and 15 other prospects. Analysts and scouts gave him positive reviews for his freakish athleticism, explosive burst, large frame, outstanding power and strength, ability to play zone coverage, and character. The only criticisms he received were due to his below-average instincts and lack of consistency. He was also ranked the top defensive end out of the 148 available by NFLDraftScout.com, was ranked the fourth best outside linebacker by Sports Illustrated, the fifth best edge rusher by NFL analyst Charles Davis, and was ranked the second best edge rusher by NFL analyst Mike Mayock.
On May 15, 2015, the Steelers signed Dupree to a four-year contract worth $9.22 million with $8.63 million guaranteed and a signing bonus of $4.97 million.
He began his rookie season as the backup left outside linebacker behind veteran Arthur Moats. Dupree made his professional regular season debut in the Steelers' regular-season opener against the New England Patriots and finished the 28–21 loss with two solo tackles and sacked Tom Brady. The next game, he made a season-high four combined tackles and a sack during the Steelers' 43–18 victory over the San Francisco 49ers. On November 29, 2015, he made his first career start against the Seattle Seahawks and made one solo tackle. He finished his rookie season with 26 combined tackles, four sacks, and a pass deflection while playing in all 16 regular-season games and five starts.