The pick was announced by Devils Hall of Fame goaltender Martin Brodeur, who was taken in the 1990 draft in Vancouver.
Hughes joins his brother Quinn, a rookie defenseman for the Vancouver Canucks, in the NHL. The Hughes brothers join the Tkachuks (Matthew and Brady) as the only pairs of brothers selected in the top 10 of the draft, according to the Elias Sports Bureau.
Like Matthews, Hughes is a product of the USA Hockey National Development Program. Hughes holds that program's records for career points (154) and goals (228). He represented the U.S. four times in international competition, most recently at the IIHF world championships.
At 5-foot-10, there have been questions about Hughes' size and how his speedy, playmaking game will transfer to the NHL. He has drawn comparisons to another American player who went first overall, Patrick Kane of the Chicago Blackhawks, who is also listed at 5-10.
"I feel like when smaller players come into the league and they have that kind of offensive game, it seems to be easy to compare him to a guy like me. But I think he does a lot of things better than I do, to be honest with you," Kane told ESPN at the Winter Classic. "I love the way he's always moving. He's always skating. Even if he's not near the puck or near the action, he's still got his speed. He's coming into the zone with a lot of movement and speed to his game. Seems like an off-the-charts skater. Seems like he's going to have a good career."
Hughes played with Kane at the world championships, and he was humbled by the praise.
"At first, your reaction is, 'You're lying, man.' He's a guy that has [Stanley] Cups, Hart Trophies, Art Rosses. You name it, he's got it," Hughes said. "For him to be talking about me like that ... it's really nice."
The Blackhawks were one of the final three teams with a shot at drafting Hughes, the most coveted player in this year's draft; fans used the phrase "Lose For Hughes" to describe their teams' attempts at tanking for better lottery odds.
Chicago, New Jersey and the New York Rangers were the final three teams in the lottery. The Devils had the third-best odds to win the lottery (11.5%), and they won it for the second time in three seasons. They drafted Swiss center Nico Hischier in 2017 at No. 1 overall.
Devils general manager Ray Shero said Hughes' selection marked "a special day for our franchise."
The Rangers, who had the sixth-best chance (7.5%) at the first overall pick, moved up to No. 2 overall. The Devils effectively determined whom their rival would select -- either Hughes or Finnish winger Kaapo Kakko, the two most prized players in the draft.
"Obviously, Kaapo Kakko had a great year ... but I was pretty confident and pretty calm, cool, collected through the whole process," said Hughes, who had a lengthy dinner with Shero during the pre-draft combine in Buffalo this month. "I've said this like eight times already, but I'm pumped to be a Devil and I'm so excited."
The Rangers followed the Hughes selection by drafting Kakko, a 6-2 winger who helped Finland complete an international gold-medal sweep at the world championships, world juniors and under-18 tournament. He had 22 goals in the Finnish Elite League, the most by a draft-eligible player.
The Blackhawks went with size in selecting 6-4 center Kirby Dach out of Saskatoon, Saskatchewan.
The Detroit Red Wings' selection of German defenseman Moritz Seider at No. 6 was the surprise of the draft. The 18-year-old figured he would land somewhere between Nos. 15 and 20.
"I was just shocked. My hands are shaking. My legs are still shaking," Seider said, adding that Detroit general manager Steve Yzerman told him to be calm and enjoy the moment because "I was so sweaty."
Listed at 6-3 and 208 pounds, Seider had two goals and six points in 29 games playing for Mannheim of Germany's top league, and he scored twice in two games at the world championships.
Colorado Avalanche general manager Joe Sakic, who grew up in suburban Vancouver, received a big cheer from the crowd before announcing the fourth pick. He drew an even louder cheer after selecting defenseman Bowen Byram, who played for Vancouver of the Western Hockey League.
The Los Angeles Kings rounded out the top five by selecting American center Alex Turcotte.
With the seventh pick, the Buffalo Sabres selected center Dylan Cozens, who became just the third player born in Canada's Yukon Territory ever drafted -- and the first in the first round. Cozens showed such ability that he was playing against adults as a 13-year-old in Yukon's capital, Whitehorse.
"It always felt like a far reach to me, not really achievable," Cozens said of being drafted. "But I believed it. I believed in myself that I could make this happen one day, and now that it's here, it's a crazy feeling."
Next to draft were the Oilers, who selected 6-3 defenseman Philip Broberg at No. 8. With the ninth selection, the Anaheim Ducks took center Trevor Zegras. The host Canucks concluded the top 10 picks by drafting right wing Vasili Podkolzin.
The first round featured only one trade, with the Arizona Coyotes giving up a second-round pick to the Philadelphia Flyers and moving up three spots to select Swedish defenseman Victor Soderstrom at 11.
There was a run of USA Hockey National Team Development Program players with picks 12 through 15. The Minnesota Wild selected forward Matthew Boldy, followed by the Florida Panthers taking goalie Spencer Knight. Philadelphia chose defenseman Cameron York at 14, and the Montreal Canadiens drafted Cole Caufield, who at 5-7 scored an NTPD-record 72 goals last season.
Knight became only the third goalie selected in the first round over the past seven years.
The Associated Press contributed to this report.