The investment would create 70,000 new jobs over 20 years, an alliance of business, political and public sector leaders said.
They are calling for the line from Crewe to north Wales to be electrified.
The campaign - called Growth Track 360 -  is backed by the region's eight councils and business groups.
It said the investment would help "unlock the region's full economic potential", ensuring it becomes an integral part of the Northern Powerhouse, which aims to attract investment into northern cities and towns.
It is calling for:
The campaign - driven by the North Wales and Mersey Dee Rail Task Force (NW&MD) - will now lobby senior rail industry figures and present the case for better rail infrastructure to senior government figures in London and Cardiff.
Councillor Derek Butler, chairman of the Mersey Dee Alliance and cabinet member for economic development at Flintshire council, said it was "vital" for the region to attract inward investment.
"We have economic and business assets of national and international significance but cannot make the most of these without a rail system which meets our needs for the future," he added.
Ashley Rogers, chairman of the North Wales Business Council, said every community in the region would benefit "massively".
"We cannot afford for this part of the UK to become a Cinderella region, left behind in the race for investment and in the government's ambitions for a Northern Powerhouse," he said.
Colin Brew, chief executive of West Cheshire and North Wales Chamber of Commerce, said: "Additional capacity and faster journey times on our rail network will reduce road congestion and massively improve commuter, tourist and freight movements across the region."
The Welsh Government's economy and infrastructure secretary Ken Skates, added: "Connecting people to jobs and businesses to growth opportunities is a must if the economy of north Wales is to continue to grow and reach its undoubted potential."
The £55.7bn HS2 project aims to create a new high-speed line to link London to Birmingham by 2026, with routes to Manchester and Leeds by 2033.
A campaign has been launched to secure £1bn of rail improvements for north Wales and Cheshire to help link the region with the planned HS2 line.