The US entertainment giant behind TV hits such as The Simpsons and Family Guy formally notified the European Commission of its bid - triggering the process by which the proposed deal will come under regulatory scrutiny.
The move means that Karen Bradley, the Secretary of State for Culture, Media and Sport, now has 10 working days to refer the deal to the media and telecoms regulator Ofcom.
At the same time, the competition authorities in Brussels have 30 days in which to make a preliminary decision on the transaction.
Within moments of the deal being formally notified to the Commission, Ms Bradley said in a statement that she was "minded to" refer the deal to Ofcom.
She (Munich: SOQ.MU - news) said: "I am 'minded to' issue a Europe Intervention Notice on the basis that I have concerns that there may be public interest considerations - as set out in the Enterprise Act 2002 - that are relevant to this proposed merger that warrant further investigation.
"To be clear - I have not taken a final decision on intervention at this stage."
A spokesperson for 21st Century Fox said: "We note the statement issued by the Secretary of State following formal notification of the proposed transaction.
"As we have previously indicated, we anticipate regulators will undertake a thorough review of the transaction, and we look forward to engaging with them as appropriate.
"We believe the combination of 21st Century Fox and Sky will create a company best suited to compete in a rapidly evolving industry, and are confident that the transaction will be approved based on a compelling fact set."
It is widely expected that the European Commission is likely to give the deal the green light because when News Corporation (Frankfurt: A1W048 - news) - the then owner of 21st Century Fox - sought to take full control of Sky in 2010, Brussels had no problem with the deal.
That would leave any decision on whether or not to block the deal with Ms Bradley.
If asked to look at the deal, Ofcom must report back within 40 days.
If it registers no concerns, Ms Bradley must clear the takeover.
But, should the regulator raise concerns, Ms Bradley would then have to decide whether to accept undertakings from 21st Century Fox to address them.
That happened in 2011, when News Corporation's bid for Sky resulted in a deal to spin off Sky News into a separate company, before News Corporation abandoned its proposals following revelations of phone hacking at the News of the World, which was owned by the company.
Pressure has been mounting on the Secretary of State to refer the deal to Ofcom ever since 21st Century Fox announced proposals to take full control of Sky just before Christmas.
A group of politicians including Ed Miliband, the former Labour leader and Sir Vince Cable, the former business secretary, have urged her to block the deal and a number of Labour MPs made similar points to Matt Hancock, the minister of state for digital and culture policy, when he faced questions in the Commons on the matter days after 21st Century Fox had first made clear its intention to take full control of Sky.
He added: "The role of Secretary of State here is a quasi-judicial one and it's important that she acts independently and is not subjected to improper influence."
If Ms Bradley does refer the deal to Ofcom, the regulator will be asked to look into whether a takeover of Sky would damage media plurality in the UK.
This is thought less likely to be an issue than in 2011 because a deal would have brought together Sky with News Corporation's other UK media assets, including The Sun, The Times and The Sunday Times.
Since then, News Corporation has broken itself into two companies.
News Corporation owns the UK newspaper assets and other titles around the world including the Wall Street Journal, The Australian and the New York Post, as well as the book publisher HarperCollins.
The other company, 21st Century Fox, owns no other UK media assets other than its 39.1% shareholding in Sky, and James Murdoch, chief executive of 21st Century Fox, has said he expects the deal to pass "regulatory muster".
However, a referral is thought likely.
Sharon White, the Ofcom chief executive, wrote to Mr Miliband last month saying that it was "appropriate" to consider the implications of a takeover.
Mr Murdoch, who is also chairman of Sky, told a media conference in London this week that the takeover would secure hundreds of millions of pounds of annual investment and would ensure Britain's creative industry could compete more effectively overseas.
He told the Enders Analysis conference: "Together, 21st Century Fox and Sky invested around £700m last year in original production in the UK alone.
"We intend to continue at least that level of investment while building on Sky's already outstanding original content pipeline."
Opponents of the deal, though, are also calling on Ofcom to carry out another investigation into whether 21st Century Fox is "fit and proper" to hold a UK broadcasting licence.