The Furkareuss rises east of Furka Pass (2,429 m), early joined by the Blaubergbach (sourced by two mountain lakes on 2,649 m) and several other creeks sourced by still existing glaciers, such as Sidelengletscher (3,170 m), Tiefengletscher (3,285 m) in the north, and Muttengletscher (2,908 m) and Witenwassergletscher (2,805 m) in the south, and eventually forms the east–west valley called Urseren, passing Realp at halfway through the valley at 1,540 m in eastern direction until its eastern end at Andermatt.

Downstream of Andermatt the Reuss joins at 1,429 m the village creek Unteralpreuss, finally turns to the north, and passes through the 3 km-long narrow and deep Schöllenen Gorge and under the legendary Devil's Bridge (1,120 m).

From here it forms the main valley of the canton of Uri, the Urner Reusstal, passing below Wassen (840 m), Gurtnellen (720 m), Amsteg and Silenen (500 m), and through Erstfeld (460 m), past Attinghausen and Altdorf (440 m), joining the southernmost part of Lake Lucerne (the Urnersee) between Flüelen and Seedorf (434 m).

Within Aargau, the Reuss flows past Aristau, Jonen, Rottenschwil, Unterlunkhofen, Hermetschwil-Staffeln, here forming Flachsee (380 m), and onward to Zufikon, Bremgarten (370 m).

From Bremgarten, the Reuss meanders between the villages of Eggenwil, Fischbach-Göslikon, Künten, Niederwil, to Stetten (352 m), flowing past Tägerig, Mellingen (350 m), Birrhard (340 m), Mülligen, Birmenstorf and between Windisch and Gebenstorf, finally joining the Aare just downstream of Brugg, at 327 m. After the confluence the river continues as the Aare, which flows into the Rhine at Koblenz.

The catchment area of the upper Reuss includes almost the entire canton of Uri (with the exception of the Urner Boden, and in the uppermost part of the Gotthardreuss a portion of Ticino (Airolo municipality).

The highest point of the drainage basin is the summit of Dammastock, at elevation 3,630 m. The basin of the lower Reuss adds the catchment areas of other tributaries of Lake Lucerne as well as that of the Kleine Emme, including most of Nidwalden and Obwalden, and parts of Schwyz, Lucerne and Zug.

Reuss and its tributaries, with length and catchment area, from mouth to source (incomplete): Ptolemy records the river's pre-Germanic name as Silana (whence the name of Silenen).

This resulted in an immense increase of the strategic value of the Reuss valley, as reflected in the grant of imperial immediacy to Uri and the wider political backdrop of the foundation of the Old Swiss Confederacy.

The river was important as waterway for traffic between Lucerne and Zurzach, and via Aare and Rhine to Basel, until the construction of transit roads in the 18th century.

River crossings by ferry in the medieval period were at Lunkhofen (mentioned 1160), Windisch, Sins, Mühlau, Oberrüti, and Dietwil.

By the end of the 20th century, there were more than a dozen crossings of the lower Reuss, including a number of railway and motorway bridges.