Hojlund brace as Man Utd beat Plzen in Europa League
The hosts took the lead shortly after half-time, but Hojlund levelled on 62 minutes, six minutes after replacing Marcus Rashford, when the Danish striker tapped in Amad Diallo's deflected shot.
Two minutes from time, he beat Plzen goalkeeper Martin Jedlicka again with a clinical finish, turning around his marker after United captain Bruno Fernandes had found him inside the box with a clever free-kick.
Matej Vydra, a former Watford, West Brom, Reading, Derby and Burnley forward, opened the scoring for the hosts with a close-range finish three minutes after half-time.
Pavel Sulc found Vydra facing an empty net after he had intercepted United goalkeeper Andre Onana's pass inside the box.
The goal was a wake-up call for United manager Ruben Amorim, who made three replacements in its wake, including Hojlund.
"It was not a great game," said Amorim, before praising the substitutes.
"They changed the game. They are there to do that so I'm pleased with that."
He added he was happy with the outcome: "It was important not to give up so that is a great message."
The former Sporting Lisbon boss replaced the sacked Eric ten Hag in November, but the chilly evening in Plzen showed United still have some way to go.
Both teams came into the match with nine points from five Europa League games, and they took time to find their pace.
Fernandes had the first shot on target half an hour into the game, but Jedlicka parried his low right-footed effort from the edge of the box.
Onana watched Cheick Souare's shot curl just past the top corner of his goal two minutes before the break.
United substitutes Mason Mount and Antony were denied by Jedlicka in the second half, with Mount failing to beat the 'keeper twice from close range.
But Hojlund turned the match on its head to put United in a strong position for direct qualification to the last 16.
"We didn't have so much time to work on this type of game. We were controlling the game but didn't have the pace (in the first half)," said Amorim.
"We want to improve and we want to improve really fast," he added.
United next face Rangers at Old Trafford on January 23.