Tony Blair said insisted independence is not in Scotland's interest as he argued a "really capable" opposition is needed to challenge the SNP in Scotland.
The former Labour Prime Minister was speaking as 17 successive polls have given a majority in favour of independence and that Nicola Sturgeon's party is on course for a fourth term in government after next year's Holyrood election.
"We had a referendum that rejected Scottish independence, but Brexit put it back on the agenda again," he said.
"And it's going to require very careful management. The truth of the matter is it's still not in Scotland's interest to separate from England.
"There are huge economic and political reasons for the United Kingdom to stay the United Kingdom but we're going to have to examine whether there's different constitutional settlements.
"I also think it's incredibly important, the single most important thing politically to my mind, is that we get a really capable opposition in Scotland - which should be the Labour Party - that's capable of contesting the Scottish nationalist position in Scotland in a way that prevents them from doing what they do at the moment, which is govern Scotland but pretend they're in opposition.
"So pretend all the problems are going to be resolved by independence, when actually the Scottish Government itself has in its power the vast amount of the levers that they need to change Scotland residing in the Scottish devolution settlement."
Blair said it is "extremely difficult" to challenge the SNP on independence when the party is "virtually uncontested" in Scotland.
He said: "You've got to look at the ways which we make the case in articulate and sensible ways as to why Scotland is stronger and better off inside the UK.
"But I come back to the point which is nothing to do with Boris Johnson, it's actually more to do with the Labour Party.
"How do you make the Labour Party back into a credible opposition in Scotland? Because while the SNP are able to govern virtually uncontested, then it's extremely difficult to dent their position on independence.
"But that's for us to decide as the Labour Party how we're going to do that."
A series of polls have suggested a poor performance for Labour at the Holyrood election in May.
Last month Survation put it up two points to 20% support in the Holyrood constituency vote among decided voters, neck and neck with the Tories, who were up a point since November.
Labour were also at 20% (+2) on the list vote, with the Tories on 18% (+1).
Despite small dips since last month, support for the SNP was still a mammoth 53% (-1) on the constituency vote, and 41% (-1) on the list.
Also on the list, 10% of decided voters surveyed in early December backed the Greens and 7% the Liberal Democrats.
The May election is set to be fought over the choice facing Scots whether to back becoming an independent nation and rejoining the EU or remaining in the Tories' Brexit Britain.
Last week the First Minister told the EU to "keep the light on" for Scotland, predicting it will return to the bloc "soon" after voting to leave the UK in a second independence referendum.
In an early sign that 2021 will bring a renewed push for independence, the First Minister claimed Brexit would prove to be the catalyst for a future Yes vote.
Shortly after the Brexit transition period formally ended at 11pm on Hogmanay, she tweeted: "Scotland will be back soon, Europe. Keep the light on."
She attached a picture of the words "Europe" and "Scotland" attached by a love heart, which was previously projected onto the side of the EU Commission building in Brussels.
An SNP majority win at Holyrood at the election in May would dramatically increase the pressure on Boris Johnson to grant indyref2.
The Prime Minister has said he will refuse to allow any such vote while he is in office, with Sturgeon indicating she may resort to court action.
In one of her first tweets of 2021, the First Minister used the hashtag "indyref2" as she highlighted how Scotland could control its own affairs after independence. "As independent Ireland takes up her seat on the UN Security Council today, not (yet) independent Scotland is taken out of the EU against our will. Time to put ourselves in the driving seat of our own future, Scotland," she wrote.
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