Running north-west from Luton, the road passes through Bedford, bypasses Rushden, Kettering and Market Harborough, continues through Leicester, Loughborough, Derby and Matlock before passing through the Peak District to Bakewell, Buxton, Stockport, Manchester, Salford, Chorley, Preston, Lancaster, Kendal and Penrith before reaching Carlisle.

It meets the A600 and A5140 at a roundabout, then passes Bedford College and crosses the River Great Ouse as King Street.

It becomes dual-carriageway on the northern outskirts of Leicester and passes the National Space Centre in Belgrave as Abbey Lane.

The road at this point follows the Soar Valley, and is mostly on embankment or viaduct, crossing the river four times.

The road follows one of the former A6 dual-carriageway sections, passing Lockington, before meeting traffic from the south-bound M1 at junction 24a.

It reaches Litchurch near Derby College's Roundhouse site; the land on which it was built was a former gas works.

This section from the first roundabout to Station Approach (B6000) includes a 900-foot (270 m) viaduct with 180-foot (55 m) spans over the Midland Main Line.

Entering Matlock, the road passes under the railway and along a new bypass and then over the River Derwent, meeting the A615 at a roundabout.

It leaves Buxton as Fairfield Road, and heads towards Stockport slightly north-east to Dove Holes and to a roundabout with the A623.

It meets the A6015 at New Mills (Newtown) for the town centre, near the railway station and primary school, where the road enters Cheshire.

It continues north-west towards Piccadilly Gardens, a major public square and bus station.

To the immediate right of this point is the Northern Quarter, an eclectic and bohemian neighbourhood containing cafes, bars and alternative stores.

Here the road is called Chapel Street as it leaves Manchester City Centre and enters Salford.

Where the original Salford Royal Hospital stands (now flats) at its junction with Adelphi Street, its name changes to the Crescent.

It then continues as the dual carriageway Broad Street through Pendleton and past the junction with Langworthy Road (A5186).

At Irlams o' th' Height it departs from the dual carriageway, at the terminus of the A580 East Lancashire Road, at the border of Pendlebury.

The road passes under the M60 near the junction with the M61, near the Worsley Braided Interchange and Wardley Hall (home of the Roman Catholic Bishop of Salford) and enters Whittle Brook and Walkden as Manchester Road, passing the Linnyshaw Industrial Estate on the right.

The A6 meets the A575 (for Worsley and Farnworth) and B5232 (for Boothstown) at crossroads where the road is dual-carriageway as High Street.

It meets the A5082 (for Tyldesley and Farnworth) at crossroads near St Paul's Church, Peel, becoming Manchester Road West.

On leaving Little Hulton, the road enters the Borough of Bolton near the Chloride Battery Works.

It crosses the River Yarrow and passes the Albany Science College as Bolton Road.

From Chorley, it meets the B6229 and B5248 at Whittle-le-Woods, passing the St John the Evangelist Church and crossing the River Lostock.

It passes through Clayton Brook and crosses the M65, entering the South Ribble district, near its western terminus.

There are crossroads with the northern terminus of the A49 then a roundabout with the A582 – where the road heads north as London Way, built in the 1980s to bypass Bamber Bridge and later widened.

Through Barton, still as Garstang Road, it runs along the Preston and Wyre district boundary, converging with the West Coast Main Line and crossing the railway on a bridge.

The University of Lancaster lies in the 0.6-mile (1 km) separation between the A6 and the M6, where there is a short section of dual-carriageway on the A6 alongside the West Coast Main Line.

There is a roundabout with the A6070, and the road, which has a short section of dual-carriageway, crosses the West Coast Main Line near Yealand Conyers.

It enters Cumbria and the Westmorland and Furness unitary authority area near the Lakeland Wildlife Oasis Centre and Hale Moss.

North of Penrith, it meets the B5305 (which heads to Wigton) at the Stoneybeck roundabout situated on a new section of the A6 built for junction 41 of the M6.

Entering Carlisle, it crosses the River Petteril (near a large radio mast) then the Tyne Valley railway line.