Portions of the route through Lancashire were proposed to be upgraded to motorway standard during the mid-20th century, latterly being downgraded to significant improvements then ultimately withdrawn from consideration.

In the centre of Liverpool, a separate 0.7 miles (1.1 km) spur heads north from the roundabout junction at the entrance of the Queensway Tunnel, joining the main route at Scotland Road in Vauxhall.

From Switch Island, the A59 travels through Maghull and Lydiate, into Lancashire through Aughton and thence to Ormskirk, roughly parallel to the Merseyrail Northern Line path.

Passing Lancashire Police HQ, the road bypasses Penwortham and continues across the River Ribble into Preston, by-passing the city centre via Ring Way, where the A583 from Blackpool converges.

At Longsight Road, it passes through Salesbury until meeting A666, at which point it bypasses Billington, Whalley then Clitheroe, Chatburn and the village of Sawley before reaching Gisburn.

Past Broughton, the road meets the Skipton bypass at its western end, where it overlaps the A65 on its route between Kendal and Leeds, de-merging with the A65 further to the east.

At the top of the hill, the road crosses into the Harrogate district, at which points there is a long narrow, twisting descent, known as Kex Gill, that leads to Blubberhouses village.

The A59 then runs along the head of Fewston Reservoir and follows the route of a Roman road past the 'golf balls' at Menwith Hill, an RAF station.

The A59 then turns left at the Empress Roundabout, which is itself on the Stray, towards the suburb of Starbeck, although traffic travelling towards York is directed onto the A661 Wetherby Road to utilise the A658 Harrogate and Knaresborough Southern Bypass.

[3] Archaeological digging in 2008 showed the Roman road crossing the River Nidd on an old county bridge prior to diverging north-east of Green Hammerton, contrary to previous understanding of the route.

[4] Evidence of ditches earlier than the Roman conquest of Britain were also uncovered during the archaeological dig in 2008, suggesting a road network present in the area dating back to the Iron Age.

[6] The present day alignment between Switch Island junction and Aughton, Lancashire via Maghull was non-existent prior to the 20th century, with the connecting roads being typically smaller lanes which still exist today.

[22] The A59 stretch of the Skipton Bypass was opened in 1981 at an estimated cost of £16.4 million (equivalent to £79,399,121 in 2023),[23] crossing the B6265 north of the town and providing relief to traffic congestion.

It was closed again due to a landslip in May 2018 and local planners have stated that a new section of road should be built to the north of the current route on the other side of a very small and narrow valley.

By 1963, Lancashire County Council had dropped the plans for a motorway of this nature,[citation needed] instead deciding to focus later efforts during the mid-1970s on proposing a scheme to improve the A59 link between Liverpool and Preston.

[41] A report by The Sunday Times in 2004 branded a section of road between the towns of Skipton and Harrogate as being "the most hazardous primary route in the nation", suggesting that the cost to implement safety measures to reduce the number of incidents could be in the region of £3 million.

[44] There were renewed calls in 2017 to improve the A59 in Ribble Valley, Lancashire, with MP Nigel Evans describing the A59 as a "dangerous road" whilst requesting the police carry out a full audit of accidents in an effort to tackle the problem.