The mainline was built between 1793 and 1805, to improve the route from the Midlands to London, by-passing the upper reaches of the River Thames near Oxford, thus shortening the journey.

[1] The three bridges are an overlapping arrangement allowing the routes of the Grand Junction Canal, Great Western and Brentford Railway, and Windmill Lane to cross.

In 1791–92, two surveys of a route from Brentford on the Thames to Braunston on the Oxford Canal were carried out, first by James Barnes and then by William Jessop.

The Grand Junction Canal Act 1793 authorised the company to raise up to £600,000 to fund construction of the main line from where the eastern branch of the River Brent enters the Thames adjoining Syon Park in the parish of Brentford, to the Oxford Canal at Braunston.

In 1799, William Jessop designed a three-arch masonry aqueduct and embankment to cross the river and replace the locks.

The Grand Junction Canal had reduced the distance to London from the Midlands by 60 miles (100 km)—via Oxford and the River Thames—and made the journey reliable.

As a result, it thrived: in 1810 it carried 343,560 tons of goods through London, with roughly equal amounts into and out of the capital.

The link to Northampton was made by a tramroad transferred from Blisworth Tunnel, with the 5-mile (8 km) canal from Gayton being opened in 1815.

The 6+1⁄2-mile (10 km) navigable feeder from Wendover to the summit level at Tring was opened in 1799, while the 10+1⁄2-mile (17 km) Buckingham branch, an extension of the original proposal for a link to the main road at Old Stratford, was opened in 1801: both eventually fell into disuse, though the Wendover Arm is undergoing active restoration, and part of it is again navigable.

The importance of trade between London and the Midlands meant that railway competition was an early threat to this canal compared with others in the country.

To cope with the traffic volumes, the locks at Stoke Bruerne were duplicated in 1835, and new larger reservoirs built at Tring to ease a serious water shortage.

In 1848 the Grand Junction entered the carrying trade, pitting its boats directly against the railway competition.

By 1871 the tunnels at Braunston and Blisworth were becoming bottlenecks and steam tugs were provided to tow strings of waiting boats through.

Consideration was given to constructing other inclined planes as part of a plan to enlarge the canals to carry 80-ton barges, but no more were built.

Concerns began to develop about the state of repair of the canal via Warwick to Birmingham, on which the Grand Junction was reliant for a through route.