The route was originally part of the Great Western Railway's main line from London Paddington to Birmingham Snow Hill, Wolverhampton Low Level and Birkenhead Woodside.

What is now the Chiltern Main Line was built in three key phases by the Great Western Railway (GWR) between 1852 and 1910: During the heyday of the route, many prestigious trains ran from Paddington to the north-west of England, via the Joint Line; these reached Wolverhampton, Shrewsbury, Wrexham General, Chester and Birkenhead Woodside.

All local trains were diverted to Marylebone in 1963 and operated by four-car Class 115 diesel multiple units (DMUs) and the main-line platforms at Greenford, on the New North route between Old Oak Common and Northolt Junction, were closed.

After the GCR main line was closed between Calvert and Rugby Central in September 1966, some trains from the South Coast were diverted north of Banbury via the route.

On 6 March 1967,[9] after completion of the WCML electrification, express trains from Paddington to Birmingham/Wolverhampton/Birkenhead were discontinued under The Reshaping of British Railways.

In 1968, the line between Princes Risborough and Aynho Junction was reduced to single track and only a basic two-hourly DMU service between Marylebone and Banbury remained to serve Bicester.

In 1977, the Parliamentary Select Committee on Nationalised Industries recommended considering electrification of more of the rail network and, by 1979, BR presented a range of options to electrify numerous routes by 2000.

[12] With the sectorisation of British Rail in the mid-1980s, operations south of Banbury fell under the control of Network SouthEast in 1986, under the Thames & Chiltern sub-sector; this was split later into two constituent parts.

Birmingham Snow Hill reopened in 1987, on a much smaller scale than the original, beneath a multi-storey car park; its tunnel was reinstated and new platforms added to the through lines at Moor Street, where the terminus was taken out of use.

The opening of the extension of the parallel M40 motorway from Oxford to Birmingham in 1991 spawned development in towns along the northern section of the route, notably Bicester, Banbury, Leamington Spa and Warwick.

In 1993, Marylebone-Banbury services were extended to Snow Hill, calling at Leamington Spa, Warwick, Solihull and Moor Street, initially on a two-hourly frequency; these were increased to hourly in the following year.

[15] Most of the route from Birmingham Snow Hill to Wolverhampton is now used by the Midland Metro light-rail system, which diverges from Network Rail's Jewellery Line at The Hawthorns.

In September 2006, Chiltern completed its Evergreen 2 upgrade project, carried out by Carillion, which realigned the track through Beaconsfield to increase non-stop speeds from 40 to 75 miles per hour (64 to 121 km/h), installed additional signals between High Wycombe and Bicester North and between Princes Risborough and Aylesbury, and added two platforms (Nos 5 and 6) at Marylebone, on the site of the daytime carriage sidings, replaced by the new Wembley Light Maintenance Depot, just south and west of Wembley Stadium station.

At weekends during 2008, when major engineering works were taking place on the WCML, the line was used by Virgin Trains' London Euston – Birmingham International Blockade Buster service via Willesden, Acton Main Line, Ealing Broadway, Greenford, High Wycombe, Banbury and Coventry, using pairs of five-car Class 221 Super Voyager sets.

[22][23][24] The delay to the full service was due to works in the Wolvercote tunnel, which were specifically scheduled to minimise disruption to roosting bats.

[30] This compares to roughly 85 minutes for the fastest Euston-Birmingham New Street trains, via the West Coast Main Line.

Chiltern Railways chairman Adrian Shooter said, "This is the biggest passenger rail project for several generations not to call on the taxpayer for support.

Working closely with Network Rail, we are going to create a new main line railway for the people of Oxfordshire and the Midlands.

This deal demonstrates that real improvements to rail services can be paid for without public subsidy by attracting people out of their cars and on to trains."

Network Rail said its investment will be reimbursed by a 'facility charge' over the next 30 years, by Chiltern Railways, whose franchise expires in December 2021, and then by the future franchisee.

The infrastructure upgrade was carried out by main contractor BAM Nuttall, in partnership with Jarvis and WS Atkins.