The Conservatives took the seat, which had been Labour-held since it was formed in 1974, with a majority of 6,940.
Boris Johnson hailed the outcome as “very encouraging”, while Labour leader Sir Keir Starmer acknowledged that it was an “absolutely shattering” blow.
Conservative candidate Jill Mortimer gained 15,529 votes – more than half the total cast – with Labour’s Dr Paul Williams trailing on 8,589.
The result was announced early on Friday morning, meaning Scots had already voted by the time they knew which party had won in the seat.
Now Scottish MPs have suggested the result is a sign of endorsement in the UK Government, while others have claimed it reiterates the need for a progressive alliance.
Tory Borders MP John Lamont MP claimed it showed the Labour party had lost communities across the UK.
He said: "Just like we have seen over the past 20 years in Scotland, Labour have taken communities for granted across the UK and are paying for it at the ballot box.
"Voters want politicians to focus on their priorities. The Labour Party are completely out of touch with them.
"The people of Hartlepool see the UK Government delivering on the issues that matter, like the world-leading vaccine rollout, protecting jobs through the furlough scheme, and seeing the UK strike trade deals with our allies around the world."
Lib Dem MP Alister Carmichael MP claimed it was about poor work by Labour, but that parties now needed to work together to defeat the Tories in Westminster.
He said: “It is always dangerous to read too much into one by-election result, but it seems clear that North-East England is enjoying the attention they are getting from the Conservative Party after years of neglect from Labour.
“The Conservatives will have to deliver on the promises they are making.
“If progressive parties are to work together, then that will require Labour to fall in behind the case for proportional representation."
Labour’s shadow communities secretary Steve Reed admitted the Hartlepool result was “absolutely shattering”, but insisted Sir Keir’s strategy was sound.
He said: “I’m very comfortable that we now have a leader that the country could see as an alternative prime minister – the problem is the Labour Party itself.
“What this shows is that, although we have started to change since the cataclysm of the last general election, that change has clearly not gone far enough in order to win back the trust of the voters.”
Visiting the constituency on Friday morning, the Prime Minister told reporters it was a mandate “for the whole of the country”.
He said: “If there is a lesson out of this whole election campaign across the whole of the UK, it is that the public want us to get on with focusing on their needs and their priorities, coming through the pandemic and making sure we build back better.”