The contest for the devolved assembly in Belfast could see a pro-Irish nationalist party win for the first time in the troubled history of the British province.
The results, expected from Friday, could have huge constitutional implications for the four-nation UK's future, with predicted victors Sinn Fein committed to a vote on reunification with Ireland.
Voters are electing councils in Scotland, Wales and much of England, with Johnson facing a potentially pivotal mid-term popularity test.
Poor results could reignite simmering discontent within his ruling Conservatives about his leadership, after a string of recent scandals.
The prime minister voted in central London with his dog Dilyn, while the main UK opposition Labour leader Keir Starmer cast his ballot in the north of the capital with his wife, Victoria.
Johnson, 57, won a landslide 2019 general election victory by vowing to take the UK out of the European Union, and reverse rampant regional inequality.
Despite making good on his Brexit pledge, the pandemic largely stalled his domestic plans.
But his position has been put in jeopardy because of anger at lockdown-breaking parties at his Downing Street office and the steeply rising cost of living.
The polls, which close at 2100 GMT, should also point to whether Labour poses a serious threat, as it tries to make inroads across England despite defending the many gains it made at the last local elections in 2018.
Labour is bidding to leapfrog the Conservatives into second place in Scotland, behind the pro-independence Scottish National Party (SNP), and remain the largest party in Wales, where 16 and 17-year-olds are eligible to vote for the first time.
The contest for Northern Ireland's power-sharing assembly is set to capture attention, after numerous polls put Sinn Fein ahead.
A University of Liverpool poll reported Tuesday it remained on target to win comfortably with over a quarter of the vote.
The pro-UK Democratic Unionist Party (DUP) and cross-community Alliance Party were tied for second.
Deirdre Heenan, professor of social policy at Ulster University, said there was a feeling the election "really is momentous".
"It will be a sea change if a nationalist becomes first minister," she told AFP.
Sinn Fein -- the IRA's former political wing -- has dialled down its calls for Irish unity during campaigning, saying it is "not fixated" on a date for a sovereignty poll, instead focusing on the rising cost of living and other local issues.
Party vice president Michelle O'Neill, who voted in County Tyrone, west of Belfast, has insisted voters are "looking towards the future" with pragmatism rather than the dogmatism that has long been the hallmark of Northern Irish politics.
"They're very much looking towards those of us that can work together versus those that don't want to work together," she said.
In Belfast, municipal worker John Potts, 56, said a border poll was low down people's priorities.
"Let's get Stormont (the Northern Ireland Assembly) up and running, let's sort out pay and health and education and the pandemic, and then we can have a wee chat about the constitution," he told AFP.
O'Neill's DUP rivals have sought to keep the spotlight on possible Irish reunification in the hope of bolstering their flagging fortunes.
In February, its first minister withdrew from the power-sharing government in protest at post-Brexit trade arrangements, prompting its collapse.
DUP leader Jeffrey Donaldson said after casting his vote that his party would not form a new executive unless London rips up the trading terms, known as the Northern Ireland Protocol.
"Words alone will not be sufficient," he told reporters. "I will not enter an executive until that action is taken."
In England, the Conservatives are predicted to lose hundreds of councillors and even control of long-time strongholds in London to Labour.
Johnson has tried to sideline the so-called "partygate" scandal that last month saw him become the first British prime minister to be fined for breaking the law while in office.
In Scotland, SNP leader Nicola Sturgeon is hoping that a strong performance in contests for all 32 local authorities can lay the groundwork for another independence referendum.
Johnson has repeatedly rejected the push for a second poll, after Scots in 2014 voted by 55 percent to 45 percent not to break away.