The Simplon Railway is a line that links Lausanne in Switzerland and Domodossola in Italy, via Brig. The 20 km (12 mi)-long Simplon Tunnel (opened in 1906) is a major part of it. The line between Lausanne and Vallorbe is sometimes considered to form part of the line, making it 233 km (145 mi) long.

Together with the Lötschberg Railway to its north, it forms the second most important trans-Alpine railway line in Switzerland after the Gotthard Railway, which lies to its east and is about 240 km (150 mi) long.

ETCS level 2 is expected to be installed on the line between Lausanne and Brig before 2022.

The Cossonay–Bussigny-près-Lausanne section was opened in 1855 by the Compagnie de l'Ouest-Suisse (West Switzerland Company, OS) as part of the construction of the Jura Foot Railway. The Bussigny–Lausanne connecting curve was opened in 1856. The Jougne-Eclépens Railway started work on the Cossonay–Vallorbe section in 1870. A cross-border connection to the French rail network was opened in 1875 with the completion of the tunnel under the Col de Jougne. However, the trains from France to Switzerland had to make a zig zag turn until 1915, when the opening of the Mont d’Or Tunnel and the new line to Frasne created a direct route. The SNCF initially maintained the line to Pontarlier via the Tunnel de Jougne, but this suffered significant damage in the Second World War, including the blowing up of the Tunnel de Jougne by the French army, and it was not rebuilt.

The first section of the line went in operation on 10 June 1857 when the Compagnie de l'Ouest Suisse opened the Villeneuve–Bex section. The line was completed by the OS, the Compagnie de la Ligne d'Italie ("Company of the Italian line") and the Compagnie du chemin de fer du Simplon ("Simplon Railway Company") in subsequent stages, ending with the closing of the Leuk–Brig gap in 1878. The upgrade to two continuous tracks between Lausanne and Brig was completed in 2004.

The construction of the Lötschberg Railway was completed in 1913 and, in preparation, Brig was upgraded to be a junction station. After 1919, the Sion–Brig section was electrified at 3000 Volt 16 Hertz three phase, but between 1923 and 1927 the line was electrified throughout at the modern SBB standard single-phase 15 kV 16.7 Hz AC system.

With the opening of the Lötschberg Base Tunnel in 2007, Visp station became an interchange station between services from the Bern region to Zermatt and services towards Sion. Since then all trains to and from the Base Tunnel have run over the Simplon line between Visp and Domodossola.

The first tube of the Simplon Tunnel was completed after eight years of construction and, along with the continuation of the line to Domodossola, it was opened in 1906. The connection to Domodossola included the Varzo elicoidale, which was probably the longest spiral tunnel in the world. The Simplon tunnel was electrified with 3000 Volt 16 Hertz three-phase AC power from the beginning of operations until 1930.