It runs east from Birmingham past the National Exhibition Centre and the M42, then bypasses Coventry and Rugby, where it briefly merges with the M45 until it continues to Daventry.

It then heads to Northampton and Wellingborough before running north of Rushden and Higham Ferrers and terminating at its junction with the A14 in Thrapston.

Prior to the construction of the M6 motorway, it was the main route from the Midlands to Ipswich and to the Haven ports.

It passes over the River Cole and meets the A4040 at a grade-separated junction at the Swan Shopping Centre in Yardley.

In December 2024 the new A4545 opened, replacing part of the southern section of the B4438, providing an alternative direct link to the M42.

The A45 becomes an urban road and skirts the south side of Coventry, crossing the A4114 near Allesley Park, the B4101 at Tile Hill, West Coast Main Line, A429 and B4113.

Beyond here the road takes a more rural nature, with a grade-separated junction with the A46 and the A444 (three level roundabout with underpass for the A46 and the A444, and an overpass for the A45).

This Portland stone memorial obelisk on the roundabout just north of Stretton-on-Dunsmore commemorates King George V's review of the 29th Division before they were sent to Gallipoli.

The road heads west past Dodford and then bypasses Weedon Bec, crossing the West Coast Main Line and Grand Union Canal and then meets the A5 at a roundabout constructed as part of the Daventry Development Link Road realignment which opened on 15 November 2018.

It then meets the older route (made of sections of the A5076 and A4500) at the A45 / A508 grade-separated junction, near Northampton High School.

The road then meets the Wellingborough bypass (A509) at a roundabout, although there is a segregated turn lane for westbound traffic wishing to continue on the A45.

It runs concurrently with the A509 to the grade-separated junction near the bridge over the River Nene, where the A509 exits south near Irchester Country Park.