Prime Minister Theresa May will sign off the Swansea Bay City Region deal later, insisting she wants Wales “at the forefront of science and innovation”.
The plan is expected to create more than 10,000 jobs and trigger almost £1.3bn investment in the region.
Mrs May said it would “benefit the whole of Wales”.
It comes as First Minister Carwyn Jones told the Guardian Mrs May had a “tin ear” on issues of devolution.
He told the newspaper Westminster would replace the EU at the heart of voters’ frustrations at having their affairs managed from afar.
“They are giving the impression sometimes that they do not listen,” he added.
Downing Street said Mrs May’s visits to the four nations, which begins in Wales, would ensure the government was “engaging and listening to people from right across the nation” before triggering Article 50 to leave the European Union.
Speaking ahead of the city deal signing the prime minister said: “Wales’ universities already have an excellent international reputation.
“They attract overseas students and pioneer in research projects here and abroad.
“I also want Wales to be at the forefront of science and innovation, as demonstrated by today’s landmark city deal for Swansea.
“The deal is a great example of what can be achieved when the UK Government, the Welsh Government and local authorities work together to secure a deal that benefits the city and the whole of Wales.”
As well as the first minister, Mrs May will meet representatives from a range of sectors and businesses at the signing ceremony at Swansea’s Liberty Stadium.
The prime minster is expected to also discuss how Wales can make the most of opportunities offered by Brexit.
Welsh Secretary Alun Cairns rejected Mr Jones’ criticism of the prime minister, claiming there was an “awful lot of common ground” with the Welsh Government on Brexit.
Speaking on BBC Radio Wales, he said Ms May was in Wales for the third time within “four or five weeks”.
“That demonstrates the priority we are placing on the union,” Mr Cairns told the Good Morning Wales programme.
“This is about getting the right deal for the whole of the United Kingdom.”
Projects in Swansea, Carmarthenshire, Neath Port Talbot and Pembrokeshire
- Connecting renewable and conventional energy firms digitally and developing new systems and storage processes
- A “cloud” enterprise zone to attract data companies
- Using the internet to improve health diagnostics, manage data and create personal treatment plans and tele-care
- A steel science centre
Rob Stewart, leader of the Swansea Bay City Region and Swansea council, said: “This is among the biggest investments Wales has ever seen, so it’s a historic day for the Swansea Bay City Region.”
Speaking ahead of the signing, Mr Jones said: “We have pushed long and hard for this city deal to be signed and have given it our strongest possible backing with £125m of Welsh Government investment.
“This is a package which will deliver jobs and economic growth for all of south west Wales, with clear benefits for all the areas involved.
“Today’s announcement is a transformative deal that will drive the regional economy in a new direction, supported by high-quality jobs and a digital infrastructure.”
Theresa May in Wales to sign £1.3bn Swansea Bay City deal}