The main line ran from London via Hitchin, Peterborough, and Grantham, to York, a loop line from Peterborough to Bawtry south of Doncaster via Boston and Lincoln, and branch lines to Sheffield and Wakefield.
The first section of line to be opened in 1848 was between Louth and Grimsby. This was followed in 1849 by Peterborough to Doncaster via Lincoln. In 1850 the line was opened to Peterborough from a temporary station at Maiden Lane in London and Doncaster to York via Askern. By 1852 the main line from London to Doncaster was open, as was the new London terminus of Kings Cross. A locomotive works was completed at Doncaster in 1853.
The Peterborough-Grantham-Retford direct route was opened in 1853 and by either purchasing other railways or obtaining running powers over them, the GNR gained access to Bradford, Cambridge, Halifax, Leicester and Nottingham. By 1857, a working arrangement was made with the Manchester, Sheffield and Lincolnshire Railway (MSLR), which enabled the GNR to run London-Sheffield-Manchester express services. In 1858, the GNR line into London from Hitchin was also used by the Midland Railway. Both these developments helped to undermine the "Euston Square Confederacy" established by the London and North Western Railway.
By the late 1850s the GNR had access to all the important West Yorkshire towns. The profits gained from the coal traffic from this area to London prompted the Great Eastern and Lancashire and Yorkshire Railways to promote a bill for a trunk line from Doncaster through Lincolnshire. This was rejected by Parliament in both 1865 and 1871. The GNR pursued territorial interests outside its original areas of interest by jointly promoting a Manchester-Liverpool route with the MSLR in 1865. This grew with further expansion into Cheshire and Lancashire via its involvement with the Cheshire Lines Committee, in concert with MSLR and MR.
By the 1870s, the GNR was running a more intensive service of express trains than either the LNWR or MR. Hauled by Patrick Stirling's single driving-wheel locomotives, they were some of the fastest in the world.
Expanding rapidly through the 1860s, the GNR was most profitable in 1873. However, in 1875, the increase in revenue was out-paced by investment, which included items such as block signalling systems and interlocking, and improvements to stations and goods sidings. The railway risked over-extending itself by marginally profitable extensions to the CLC network and construction of lines in Nottinghamshire and Leicestershire under joint control with the LNWR. Access was gained to the Norfolk coast by a joint acquisition with the MR of the Eastern and Midlands Railway from 1889, the system being known as the Midland and Great Northern Joint Railway.
The GNR's role in the establishment of an Anglo-Scottish East Coast route was confirmed by establishment of the East Coast Joint Stock in 1860, whereby a common pool of passenger vehicles was operated by the GNR, North Eastern and North British Railways. The main express trains were the 10am departures from Kings Cross and Edinburgh Waverley which began running in June 1862. By the 1870s they were known as the Flying Scotsman. The GNR's trains were improved and expanded from the late 1870s, notably with the introduction of the first regular restaurant car service in 1879 and the fitting of continuous vacuum braking by 1881.
Suburban development in North London brought a rapid increase in season ticket traffic. The City was catered for by trains running to Broad Street, following reciprocal arrangements with the North London Railway set up in 1875. Widening of the London end of the main line was completed in the 1890s.
The main revenue of the GNR was derived from freight, mainly coal, for which major marshalling yards were built at Doncaster, Colwick (Nottingham), New England (Peterborough) and Ferme Park (London). For merchandise traffic, the GNR was a pioneer of the fully braked goods train.
Under the 1923 Grouping, it became part of the London and North Eastern Railway.