CJ Ujah, Adam Gemili and Darren Talbot produced a perfect first three legs to deliver the baton to Mitchell-Blake in the lead with Jamaica well back.
Usain Bolt was running his last ever race as a professional but pulled up halfway through his anchor leg while 100m silver medalist Christian Coleman could not drag the American team back ahead of the Brits.
The home quartet had hinted at their speed with a qualification time that was just 0.03s outside their national record but they were still beaten by a strong US group.
But Gemili, who had missed out on individual selection due to injury around the time of trials, ran the leg of his life on the back straight, out-doing 100m champion Justin Gatlin and ensuring Talbot on the third leg was able to run the curve out in front.
The British fans had been handed disappointment earlier in the evening as Mo Farah, like Bolt racing in his final major championship, was beaten to 5,000m gold by Ethiopia’s Muktar Edris.
And they were torn between supporting their own and desperation to see the legendary Jamaica finish in golden fashion.
But their performance was so exemplary that even a fully fit Bolt might have struggled to catch a blistering Mitchell-Blake, a fact acknowledged by BBC pundit Michael Johnson.
“This is not a win where the US drops the baton or Jamaica steps out of the zone,” Johnson said.
“They won square and fair. It was the third fastest time of all time.
“It was just an amazing performance in front of a home crowd wanting a gold medal and they delivered it on a night when everyone was here, maybe not necessarily to see this, but everyone was here.
“It’s just an amazing story for that team.”