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The A159 departs southwards from the A18 at the Queensway Roundabout in Scunthorpe. After approximately 1 mile (1.6 km), there are two Turn Off To Stay On (TOTSO) junctions in quick succession in the Ashby district of Scunthorpe. The A159 then leaves Scunthorpe, through Bottesford and Messingham.
Along its length between Scunthorpe and Gainsborough the A159 is variously named Messingham Road, Northfield Road, Scotter Road, Gainsborough Road, Leighton Road and Thonock Road. It passes through Bottesford, Messingham, Scotter, Blyton, Wharton and Thonock.
As the A159 enters Gainsborough it passes the Queen Elizabeth's High School; it continues southbound through Gainsborough, passing Gainsborough Trinity F.C.'s football ground and terminating at the roundabout with the A631 (Thorndike Way/The Flood Road) and the A156 (Ashcroft Road).
There were plans to extend the A159 north of the A18 which would see the road continue towards Scunthorpe town centre following Ashby Road and Oswald Road ending at the top of Frodingham Road at the B1216.