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The Jacksonville Jaguars selected defensive lineman Travon Walker with the first pick of the 2022 draft.
The defensive end, 21, and fellow pass rusher Aidan Hutchinson were the leading contenders to be the top pick.
The Detroit Lions took Hutchinson, also 21, with the second pick and, for the first time since 1991, the first five chosen were all defensive players.
Walker did not attend the event, held in Las Vegas after a two-year delay, but watched from a hotel in Atlanta.
Having again finished with the NFL's worst record, it was the second straight year that the Jaguars had the first pick after selecting quarterback Trevor Lawrence in 2021.
Walker emerged from hundreds of NFL hopefuls playing in the US college system last season, starting all 15 games for Georgia as they won the national championship.
Kenny Pickett was the only quarterback chosen in the first round, with the Pittsburgh graduate taken by the Pittsburgh Steelers with the 20th pick.
David Ojabo, who was born in Nigeria and raised in Scotland, was not among the first 32 picks in the first round, but the draft continues with the second and third rounds on Friday (midnight BST).
The NFL draft finally gets the Las Vegas treatment
All the glitz and glamour normally associated with what is a life-changing day for many young players returned this year after the Covid-19 pandemic put paid to plans to host the event in Las Vegas in 2020.
That year the draft was held virtually, while a watered-down version took place last year, but it finally got the Las Vegas treatment this time around, with a red-carpet stage constructed in front of the Bellagio fountains and the main stage built beside the Caesars Forum.
From this year's top prospects, 21 attended the event including Kayvon Thibodeaux, who was expected to go first earlier this year but drifted down fans' and analysts' mock drafts during the draft process.
The former Oregon defensive end was ultimately taken fifth by the New York Giants, who also took offensive tackle Evan Neal with the seventh pick.
Because of previous trades, the Giants and their fellow strugglers the New York Jets both had two picks in the top 10, and the Jets went for cornerback Ahmad 'Sauce' Gardner and wide receiver Garrett Wilson.
The biggest drama on draft day came as the Philadelphia Eagles traded the 18th pick and a third-round choice to the Tennessee Titans for AJ Brown.
The 25-year-old has been the Titans' top receiver in his first three years in the NFL but entering the final year of his rookie contract, both parties were struggling to agree on financial terms over a new deal.
Brown is set to earn a four-year deal worth $100m (£79.8m) with the Eagles, while with the 18th pick the Titans chose another receiver, Treylon Burks.