Historically, it ran from the N5 in Sens through Auxerre and Macon to Lyon. It then cannoned off the N7 and heading east through Chambé̩ry towards the French Alps, crossing the Italian border at the Col du Mont Cenis. Following the Italian Peace Treaty of 1947, the road was extended to the new Italian border south of the summit.
After an extensive detrunking programme in 1973, the N6 took over the former N5 to the Porte de Charonton in Paris. Another detrunking exercise in 2006 now means the road starts on the A86 on the outskirts of Paris and runs to Lieusant, and briefly reappears near Auxerre. The remainder of the route has been downgraded to a series of D roads and mostly shadows the A6 to Lyon, then the A43 to the Alps.