The line is fully electrified at 3,000 volts DC and is double track. In some stretches between Arona and Domodossola, the two tracks are not adjacent: the southbound line towards Milan runs directly along the shore of Lake Maggiore; the northbound line towards Domodossola is located a little inland because of the local geography. At Domodossola the electrification system changes to the Swiss system of 15,000 volts AC 16.7 Hz for the Simplon Tunnel.
The regional passenger rail service is operated by Trenord. The section between Gallarate and Milan is also served by suburban line S5. The railway is also served by long-distance Eurocity and EuroNight trains, as well as the high-speed Cisalpino trains, which connect Milan to the Swiss cities of Lausanne, Geneva, Bern and Basel.
The Domodossola–Milan line is also used by freight trains operated by Trenitalia Cargo, SBB Cargo Italia and other private companies.
The line passes through the metropolitan area to the northwest of Milan, across the plain towards Gallarate. It continues through the forests of lower Varese Province towards Lake Maggiore. After Sesto Calende it crosses the Ticino River on an iron bridge, which was opened to traffic in 1882. State road 33 (the Milan–Simplon Pass road) uses the same bridge, above the railway. From Arona, the line largely runs along the western shore of Lake Maggiore, keeping above the shore, passing through the major tourist town of Stresa. After Baveno, it enters the Toce plain and runs for about 30 km (19 mi) up the Ossola valley to Domodossola. It then approaches the Simplon Tunnel through nine tunnels including the 2,966-metre long (9,731 ft) Varzo Tunnel, which is built as a spiral in order to gain height.
