Boston had the most successful regular season in NHL history, with a record 65 triumphs and an unprecedented 135 points.
But that counted for nothing as they were dumped out of the post-season on home ice by a Panthers team that was the eighth seed in the East.
"It really is the biggest upset in NHL history, to every single person other than those in that (locker) room," said Panthers winger Matthew Tkachuk, whose game five overtime winner started their remarkable comeback in the series.
"What an unbelievable effort, it is one of those legacy games for our team and our franchise, we just did what nobody in the world thought we could do."
Boston had been 3-1 up in the best-of-seven series but needing just another win, they lost the last three games.
Adding to the agony, the Bruins had come back from 2-0 down on Sunday to lead 3-2 with one minute remaining, only for Brandon Montour's one-timer to force overtime.
Carter Verhaeghe then scored at 8:35 in overtime to silence the raucous crowd in the TD Garden and prompt wild on-ice celebrations from the visiting Panthers.
It was also the start of what will be a painful post-mortem for the Bruins.
"The way it ended, it didn't matter how it ended, the season is over," said Bruins coach Jim Montgomery.
"I guess the words that come to mind right now are disappointment, confusion."
Despite the stunning exit, Montgomery said he was proud of what the team had been able to achieve.
"The other part is if you start looking at the season, it was an honour to coach that group. I know we didn't get to where we wanted, I get that, but their professionalism, work ethic and commitment was a joy to be around," he said.
The future of the Bruins' pair of 37-year-olds - captain Patrice Bergeron, who skated to center ice to acknowledge the team's fans after the game and Czech David Krejci - remains uncertain after the loss.
Asked whether this was the end of their time with the club, Montgomery said: "I've no idea, that's up to them".
The Panthers will now face the Toronto Maple Leafs in the Eastern Conference second round.
Panthers head coach Paul Maurice had no doubt about the magnitude of his team's achievement.
"I don't think you can find a harder team to play against than the Boston Bruins, they are just that good. There isn't a weakness in their game," he said.
"The players now have a shared experience of what heart is. We will cut that video, keep that video and use it at training camp and it will make us better for five years, that's how hard it was."
