Shea Theodore also scored for Vegas, and Jonathan Marchessault had a goal with 0.6 seconds left in the three-goal first period to send the Bruins to their locker room to the boos of the hometown crowd.
Robin Lehner made 23 saves for the Vegas, which began a four-game East Coast trip with their fifth win in six games.
''It was a good start to a tough road trip,'' coach Peter DeBoer said.
Hours after the Bruins put leading scorer Brad Marchand in the COVID-19 protocol, and one day after coach Bruce Cassidy returned from his positive test, the Bruins snapped a two-game winning streak.
''We obviously know what a good player Marchand is,'' DeBoer said, nothing that forward Craig Smith also entered the protocol, hurting the Bruins' depth.
''This season has been all about managing injuries and guys in and out of the lineup,'' he said. ''We try to concentrate on our own team. That's all you can do.''
Patrice Bergeron scored for Boston, which fell behind 4-0 and pulled Jeremy Swayman with 2:43 left but could not get any closer.
''You're going to have tough breaks some times. It's how you respond,'' said Swayman, who stopped 21 shots. ''It's all about competing until the last whistle blows.
Theodore scored with seven minutes left in the first. Two minutes later, Chandler Stephenson made a long pass to Pacioretty, who beat Swayman to make it 2-0.
The Golden Knights got a power play with 19 seconds left in the period. As the final second drained from the clock, Marchessault's pass deflected off two Bruins and through Swayman's legs to make it 3-0.
After booing the team off the ice at the end of the first, the crowd tried to fire it up to start the second with a chant of ''Let's go Bruins!'' But five minutes in, Pacioretty scored again for his 58th career multigoal game. He has 12 goals in 11 games.
Stephenson had three assists, including both of Pacioretty's goals.
''You can get a sense that this is going to come and it's going to come my way,'' Pacioretty said. ''So you've got to be ready for it.''
IN THE PROTOCOL
The Bruins were the last team to play Calgary before the Flames' season was put on hold Monday due to having six players and one staffer in the COVID-19 protocol. On Tuesday, Boston put Marchand and Smith in the NHL's COVID-19 protocol. Boston recalled forwards Jack Studnicka and Oskar Steen on an emergency basis to fill out the lineup.
Golden Knights: At New Jersey on Thursday.
Bruins: Visit the Islanders on Thursday.
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