The section of A50 through Cheshire was once the main trunk road running north-south prior to the construction of the M6 in the 1960s. There were frequent delays through Holmes Chapel and Knutsford. The M6 was built, bypassing the A50 which became a road largely for local traffic, but its wide single-carriageway in places hints at its former status.
The A50 enters Cheshire from Staffordshire at Kidsgrove near the A34 crossroads. Heading west, it meets the A5011 near Alsager, before turning north. At Rode Heath, there is a junction with the A533 and shortly after a crossroads with the A534. The A50 on this section is very wide, and was originally layed out as a three-lane single-carriageway - one lane for each direction and a bi-directional overtaking lane sometimes nicknamed a "suicide lane". It is now marked out as a wide 2-lane single carriageway.
The A50 enters Holmes Chapel and there are junctions with the A54 and A535. At St. Luke's church is a narrowing of the main road which was frequently a cause of bottlenecks in the pre-motorway age. The next bottleneck was at Knutsford, with junctions of the A537 and A5033 in quick succession. The A50 continues over the busy A556 to a junction with with the M6 and M56 near Warrington.
In Warrington, the A50 meets the A56 before crossing the Manchester Ship Canal via a swing bridge. There are junctions with the A5061, A57 and A574 before the road terminates at the A49.