Johnson, 57, is already reeling after around 100 of his own MPs on Tuesday broke ranks and voted against government plans to introduce vaccine passes for large events.
It follows a torrid few weeks for the leader, whose authority has been hit by claims of corruption and reports that he and his staff broke coronavirus restrictions last Christmas.
In normal times, a by-election in the rural English constituency of North Shropshire would be a formality for Johnson’s Conservative Party, which has never lost the seat.
The constituency, which has just over 80,000 voters, returned its last Tory lawmaker with a whopping 23,000 majority.
But ahead of polls opening at 0700 GMT, Johnson is struggling to convince many to stick with him after weeks of bad headlines, prompting predictions of a historic loss.
The poll, which closes at 2200 GMT, is increasingly seen as a referendum on Johnson’s premiership, just two years after his landslide general election victory in December 2019.
Defeat would likely see MPs start filing letters of no-confidence in their leader, which could trigger an internal party vote to remove him.
The same process saw his predecessor Theresa May ousted in mid-2019 after MPs, including Johnson himself, voted against her Brexit deal in parliament.
The Liberal Democrats have the best chance of overturning the Conservatives’ huge majority, helped by Labour supporters lending them their votes to maximise Johnson’s political pain.
In the market town of Whitchurch, Martin Hill, 68, who normally votes Labour, told AFP: “I’ll be voting for the Liberal Democrats because I’m so offended by the performance of Johnson.
“It’ll be a tactical vote — I want to give Johnson a slap in the face,” added the retired chemical engineer, calling the prime minister “dishonest”.
However, some in Whitchurch were standing by Johnson and prepared to overlook the maverick former London mayor’s transgressions.
“I think Boris Johnson’s been a bit silly really… like a naughty little schoolboy,” said 67-year-old Sue Parkinson, who has voted Conservative for the last two decades.
“I don’t think it’s enough for us to say: ‘right, we want a new leader now’, because I think Boris has done an excellent job.”
The atmosphere is a far cry from May, when the Conservatives swept to an unprecedented by-election victory in the northeast England seat of Hartlepool on the back of a successful vaccine roll-out.
But the virus still dominates British life, and the arrival of the Omicron variant has again deepened the gloom before Christmas. Nearly 80,000 people tested positive for Covid-19 in a 24-hour period on Wednesday — the highest daily number since the pandemic hit Britain last year.
Britain is also suffering spiralling inflation as a result of big borrowing during lockdowns, high energy prices and bottlenecked supply chains.
With inputs from NDTV