The route passes through Alta (Norway) – Kautokeino – Hetta (Finland) – Palojoensuu – Kaaresuvanto – Gällivare (Sweden) – Porjus – Jokkmokk – Arvidsjaur – Östersund – Mora – Säffle – Åmål – Brålanda – Gothenburg ... Frederikshavn (Denmark) – Aalborg – Randers – Aarhus – Skanderborg – Vejle – Kolding – Frøslev – Flensburg (Germany) – Hamburg – Hanover – Hildesheim – Göttingen – Kassel – Fulda – Würzburg – Nuremberg – Munich – Rosenheim – Wörgl (Austria) – Innsbruck – Brenner – Fortezza (Italy) – Bolzano – Trento – Verona – Modena – Bologna – Cesena – Perugia – Fiano Romano – Naples – Salerno – Sicignano – Cosenza – Villa San Giovanni ... Messina – Catania – Siracusa – Gela.

The Swedish government proposed the extension alone in 2005 and let the E45 end at the border, partly because of lack of interest from Finnish authorities.

The gap between the end of E45 and the European route E8 was about 1 km along the existing Finnish regional road 959 Karesuvanto (FIN) – Karesuando (SWE) In August 2016, after a political proposal in 2007, the governments of Norway and Finland applied for an extension of E45 Karesuando–Kaaresuvanto–Palojoensuu–Hetta–Kautokeino–Alta.

[5] E45 sign posts were mounted starting 9 February 2018,[6] replacing route 93 in Norway, and complementing road 959, 21 and 93 in Finland.

Between Karesuando and Torsby (1370 km) the road is usually 6–8 meters wide, and goes mostly through sparsely populated forests, with occasional villages and only two cities above 10,000 people, Östersund and Mora.

In Denmark the E45 is a motorway (speed limit 110 to 130 km/h or 70 to 80 mph) from the south of Frederikshavn along the east coast of Jutland to the Denmark–Germany border.

Owing to the greater recognition of motorways and nationally or locally numbered major roads in Italy, in colloquial usage "E45" often refers to the Cesena-Orte segment,[7] possibly further expanded to include the Ravenna-Cesena section of the SS3bis (formally part of the E55, and forming together the Strada di Grande Comunicazione Ravenna-Orte) and/or the Orte-Rome segment.