Starting from Bodmin, the road runs past Liskeard, Saltash, Plymouth and Buckfastleigh to Exeter, then reemerges from its junction with the M5 motorway, ten miles north of Exeter, and heads north via Wellington, Taunton, Bridgwater, Bristol, Gloucester, Tewkesbury, Worcester, Bromsgrove, Birmingham, then bypasses Sutton Coldfield, Lichfield, Burton-upon-Trent and Derby before heading through Alfreton to end in Mansfield.
The section from Plymouth to Exeter is designated as the "Devon Expressway", and serves as a southward extension of the M5 motorway. From Exeter to Birmingham, the road is paralleled by the M5.
Between Worcester and Birmingham the A38 follows the course of a Roman road, although the construction of bypasses around some towns means the modern-day route deviates somewhat from the original dead-straight road.