Plans to dual the entire length of the A66 between the M6 at Penrith and the A1(M) at Scotch Corner have been given the go-ahead.
The existing route is 80km in length and intermittently dualled with around 30km of single carriageway within six separate sections.
On completion, the government said the project would result in an 80km route with two lanes in both directions.
National Highways said it was the biggest single investment in the north’s road network in a generation.
The route carries high levels of freight, with 25% of the traffic being HGVs, more than twice the national average for a road of this nature.
The scheme will also include junction improvements and minor improvements to the existing dual carriageway sections.
National Highways said that now the project had been signed off, it could plan for construction.
It added that preparatory archaeological works and utilities diversions were currently taking place.
Stewart Jones, National Highways project director for the A66 Northern Trans-Pennine project, said: “We are delighted to have received approval and to be able to give the people of Cumbria, County Durham and North Yorkshire some positive news.
“A lot of hard work has gone into getting us to this position. Now we can push on and deliver this project as efficiently as possible.”
He added: “We will be part of community life for the next few years, so we want to make sure we are giving back. We will be using local companies and employment during our construction work, which will help support the local economy.”
Martin Tugwell, chief executive for Transport for the North (TfN), said the announcement was “very welcome news”.
He said: “TfN set out the strategic importance of this scheme at its inquiry and it is good news to see the Secretary of State confirm the order.
“Duelling the A66 will deliver vital improvements to east-west connectivity in the North. It will remove bottlenecks along this key corridor, make the road safer and more reliable for everyone who uses it, including the high percentage of freight using the route, and connect our towns and cities to Scotland.”