It shares the A1(M) route south to Scotch Corner, from where it continues west across the Pennines, past Brough, Appleby, Kirkby Thore, Temple Sowerby and Penrith until it reaches Junction 40 of the M6 motorway at Skirsgill Interchange, where traffic going towards Western Scotland turns onto the northbound M6.

The A66 continues past Blencathra to Keswick and Cockermouth and on through the northern reaches of the Lake District before arriving at the coastal town of Workington.

The westbound section was closed due to flood damage in December 2015; when it re-opened in May 2016, the road had been permanently reduced to a single lane.

The middle 49.5 miles (79.7 km) section of the A66 between Scotch Corner on the A1(M) and Penrith on the M6 forms one of the key trans-Pennines trunk routes and has one of the worst road-safety records in the UK.

In 2002, after many years of local campaigning, the Transport Minister, John Spellar, gave support for the upgrading of the remaining single-carriageway sections by the Highways Agency.

The Highways Agency website states "Other than those already committed, the Regions did not identify any other major schemes for the A66 as high priorities to receive funding.

[9] In March 2024, Transport Secretary Mark Harper approved a £1.3 billion scheme to dual the A66 in its entirety between Scotch Corner and Penrith.

[12][13] The section of road between Scotch Corner and Penrith accounted for 70 deaths over ten years up until 2002, which was above the national average for single lane carriageways.